Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof

ABSTRACT

Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are also described in the present invention.

This application claims benefit of U.S. Provisional Patent Application Ser. No. 61/222,437, filed Jul. 1, 2009, and U.S. Provisional Patent Application Ser. No. 61/329,414, filed Apr. 29, 2010, which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to substituted azepino[b]indoles, which are melanin-concentrating hormone (MCH-1) receptor antagonists, pharmaceutical compositions including these compounds, and methods of preparation and use thereof. The compounds are useful in the treatment of obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders.

BACKGROUND OF THE INVENTION

Obesity and the multitude of co-morbidities associated with obesity such as diabetes, dyslipidemia, coronary heart disease, and certain cancers are a major concern for public health. The currently available pharmaceutical therapies for the treatment of obesity have limited efficacy and side effects that limit their use. Thus, there is a significant medical need for better pharmacotherapy for obesity.

Obesity has associated with it, economic and social costs. Obese people, an increasing proportion of most western societies, are regarded as having out of control feeding habits often associated with low self-esteem. Moreover, obese persons are more likely to have medical problems associated with or exacerbated by the excess body weight. Examples of medical conditions caused, exacerbated, or triggered by excessive weight include bone fractures, pains in the knee joints, arthritis, increased risk of hypertension, artherosclerosis, stroke, and diabetes.

Melanin-concentrating hormone (MCH) has been identified as an orexigenic peptide that exerts an effect on food intake and body weight regulation. MCH is a cyclic 19 amino acid neuropeptide expressed in the zona incerta and lateral hypothalamus in response to both energy restriction and leptin deficiency. MCH is known to stimulate feeding when injected into the lateral ventricle of rats and the mRNA for MCH is upregulated in the hypothalamus of genetically obese mice (ob/ob) and in fasted control and ob/ob animals. In addition, animals treated with MCH show increases in glucose, insulin and leptin levels, mimicking human metabolic syndrome (Gomori, “Chronic Infusion of MCH Causes Obesity in Mice,” Am. J. Physiol. Endocrinol. Metab., 284:E583 (2002)). Mice lacking MCH are hypophagic and lean with increased metabolic rate, whereas animals over-expressing MCH gain excess weight on both standard and high fat diets. MCH is thought to have effects on other nervous system functions as well (Rocksz, “Biological Examination of Melanin Concentrating Hormone 1: Multi-tasking from the Hypothalamus,” Drug News Perspect., 19(5):273 (2006)). An orphan G-protein coupled receptor (GPCR) was recently identified as a receptor for MCH. Disruption of the binding between MCH and the MCH receptor, i.e. MCH antagonism, may thus be used to counteract the effects of MCH (McBriar, “Recent Advances in the Discovery of Melanin-Concentrating Hormone Receptor Antagonists,” Curr. Opin. Drug Disc. & Dev., 9(4):496 (2006)).

The current preferred treatment for obesity as well as Type II non-insulin dependent diabetes is diet and exercise with a view toward weight reduction and improved insulin sensitivity for diabetics. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently only two medications approved for the treatment of obesity (sibutramine (MERIDIA™) and orlistat (XENICAL™).

The present invention is directed to overcoming these and other deficiencies in the art.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I):

wherein

-   R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴,     —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl is optionally substituted with from 1 to 3 substituents     independently selected at each occurrence thereof from C₁-C₃ alkyl,     halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally     substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; -   R²-R⁵ and R⁹-R¹² are each, independently, selected from the group     consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,     —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,     —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,     aryl, and heteroaryl is optionally substituted with from 1 to 3     substituents independently selected at each occurrence thereof from     C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is     optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴     and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or     heterocycle group containing from 1 to 5 heteroatoms selected from     the group consisting of oxygen, nitrogen, and sulfur; -   R⁶ is independently selected at each location from the group     consisting of H, halogen, —OR¹³, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴,     —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆     alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇     cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of     C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇     cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally     substituted with from 1 to 3 substituents independently selected at     each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶,     —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with     halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or     —NR¹⁶R¹⁷; -   R⁷ is optionally present and, if present, is selected from the group     consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,     —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,     —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,     aryl, and heteroaryl is optionally substituted with from 1 to 3     substituents independently selected at each occurrence thereof from     C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is     optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴     and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or     heterocycle group containing from 1 to 5 heteroatoms selected from     the group consisting of oxygen, nitrogen, and sulfur; -   R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴,     —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl is optionally substituted with from 1 to 3 substituents     independently selected at each occurrence thereof from C₁-C₃ alkyl,     halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally     substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; -   R¹³ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl,     wherein phenyl or benzyl is optionally substituted 1 to 3 times with     halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; -   R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl     or benzyl is optionally substituted 1 to 3 times with halogen,     cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; -   R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; -   R¹⁶ and R¹⁷ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,     —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally     substituted from 1 to 3 times with a substituent selected     independently at each occurrence thereof from the group consisting     of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; -   R¹⁸ is selected from the group consisting of H, halogen, —OR¹³,     —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴,     —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,     aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl,     C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,     heterocyclyl, aryl, and heteroaryl is optionally substituted with     from 1 to 3 substituents independently selected at each occurrence     thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl     which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl,     C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹; -   G is —NR⁸—CR⁹R¹⁰—C¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or     —CR⁹R¹⁰—C¹¹R¹²—NR⁸—, with the proviso that when G is     —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not —C(O)NR¹³R¹⁴; -   X is CR¹⁸, C(R¹⁸)₂, N, or NR¹⁸; -   Y is CR¹⁸, C, or N; -   Z is C, CH, or N; -   L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond; -   A is C, CH, or N; -   B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of     the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally     substituted with from 1 to 3 substituents selected from the group     consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆     alkyl, halogen, —CF₃, and —CN; -   n is 0, 1, 2, or 3; -   p is from 1 to 4; -   q is 0, 1, or 2; and -   represents an optional double bond, -   or an oxide thereof, a pharmaceutically acceptable salt thereof, a     solvate thereof, or prodrug thereof.

Additional aspects of the present invention include pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier and, optionally, one or more additional additive agent(s) as discussed below.

The present invention also relates to a method of treating a disease or condition which is susceptible to treatment with a MCH-1 receptor antagonist. This method involves selecting a patient with a disease or condition which is susceptible to treatment with a MCH-1 antagonist and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating obesity in a subject in need of weight loss. This method involves selecting a patient in need of weight loss and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Yet another aspect of the present invention relates to a method of treating obesity in a subject who has experienced weight loss. This method involves selecting a patient who has experienced weight loss and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a method of treating anxiety. This method involves selecting a patient with anxiety and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating depression. This method involves selecting a patient with depression and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treating non-alcoholic fatty liver disease. This method involves selecting a patient who has non-alcoholic fatty liver disease and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a process for preparation of a product compound of formula I which includes treating a first intermediate compound of formula II:

wherein Q is a halogen, under conditions effective to form the product compound.

It has now been found that compounds of formula I are MCH-1 receptor antagonists. This invention provides compounds that bind to the MCH-1 receptor with high affinity. The compounds provided by formula I are useful for the treatment of obesity, anxiety, depression, psychiatric disorders, and other disorders described herein. In particular, it is contemplated that the compounds of this invention will be effective in treating obesity, including weight loss and maintenance of weight loss in patients who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-abdominal fat), Dual Energy X-Ray Absorptiometry (DEXA), and trucal (android) fat mass. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I)

wherein

-   R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴,     —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl is optionally substituted with from 1 to 3 substituents     independently selected at each occurrence thereof from C₁-C₃ alkyl,     halogen, —CH, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally     substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; -   R²-R⁵ and R⁹-R¹² are each, independently, selected from the group     consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,     —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,     —C(O)NR¹³R¹⁴, C₁-C₆, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,     aryl, and heteroaryl is optionally substituted with from 1 to 3     substituents independently selected at each occurrence thereof from     C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is     optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴     and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or     heterocycle group containing from 1 to 5 heteroatoms selected from     the group consisting of oxygen, nitrogen, and sulfur; -   R⁶ is independently selected at each location from the group     consisting of H, halogen, —OR¹³, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴,     —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆     alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇     cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of     C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇     cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally     substituted with from 1 to 3 substituents independently selected at     each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶,     —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with     halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or     —NR¹⁶R¹⁷; -   R⁷ is optionally present and, if present, is selected from the group     consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,     —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,     —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,     aryl, and heteroaryl is optionally substituted with from 1 to 3     substituents independently selected at each occurrence thereof from     C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is     optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄     haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴     and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or     heterocycle group containing from 1 to 5 heteroatoms selected from     the group consisting of oxygen, nitrogen, and sulfur; -   R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴,     —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and     heteroaryl is optionally substituted with from 1 to 3 substituents     independently selected at each occurrence thereof from C₁-C₃ alkyl,     halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally     substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; -   R¹³ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl,     wherein phenyl or benzyl is optionally substituted 1 to 3 times with     halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; -   R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆     cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl     or benzyl is optionally substituted 1 to 3 times with halogen,     cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; -   R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; -   R¹⁶ and R¹⁷ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,     C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,     —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally     substituted from 1 to 3 times with a substituent selected     independently at each occurrence thereof from the group consisting     of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; -   R¹⁸ is selected from the group consisting of H, halogen, —OR¹³,     —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴,     —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,     aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl,     C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,     heterocyclyl, aryl, and heteroaryl is optionally substituted with     from 1 to 3 substituents independently selected at each occurrence     thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶, —NR¹⁶R¹⁷, and     phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄     alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹; -   G is —NR⁸—CR⁹R¹⁰—CR¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or     —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—, with the proviso that when G is     —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not —C(O)NR¹³R¹⁴; -   X is CR¹⁸, C(R¹⁸)₂, N, or NR¹⁸; -   Y is CR¹⁸, C, or N; -   Z is C, CH, or N; -   L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond; -   A is C, CH, or N; -   B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of     the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally     substituted with from 1 to 3 substituents selected from the group     consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆     alkyl, halogen, —CF₃, and —CN; -   n is 0, 1, 2, or 3; -   p is from 1 to 4; -   q is 0, 1, or 2; and -   represents an optional double bond, -   or an oxide thereof, a pharmaceutically acceptable salt thereof, a     solvate thereof, or prodrug thereof.

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If not defined otherwise herein, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

The term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched. When not otherwise restricted, the term refers to an alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, and the like.

The term “alkenyl” means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. In the present invention, the term “alkenyl” may also refer to a hydrocarbon chain having 2 to 6 carbons containing at least one double bond and at least one triple bond.

The term “alkynyl” means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butyryl, 3-methylbutynyl, and n-pentynyl.

The term “aryl” means an aromatic monocyclic or multi-cyclic (polycyclic) ring system of 6 to about 19 carbon atoms, preferably of 6 to about 10 carbon atoms, and includes arylalkyl groups. The ring system of the aryl group may be optionally substituted. Representative aryl groups of the present invention include, but are not limited to, groups such as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl, fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.

The term “arylalkyl” means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl, and the like.

The term “alkoxy” means groups of from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purposes of the present patent application, alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain, or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring. Thus, for example, phenyl substituted by alkoxy may be, for example,

The term “compounds of the invention”, and equivalent expressions, are meant to embrace compounds of general formula I as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, the oxides, the solvates, e.g. hydrates, and inclusion complexes of that compound, where the context so permits, as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio. Inclusion complexes are described in Remington, The Science and Practice of Pharmacy, 19th Ed. 1:176-177 (1995), which is hereby incorporated by reference in its entirety. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims. Thus, in accordance with some embodiments of the invention, a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.

The term “cycloalkyl” means a non-aromatic, saturated or unsaturated, mono- or multi-cyclic ring system of about 3 to about 7 carbon atoms, preferably of about 5 to about 7 carbon atoms, and which may include at least one double bond. Exemplary cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclophenyl, anti-bicyclopropane, and syn-tricyclopropane.

The term “cycloalkylalkyl” means an cycloalkyl-alkyl-group in which the cycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylmethyl. The alkyl radical and the cycloalkyl radical may be optionally substituted as defined herein.

The term “haloalkyl” means both branched and straight-chain alkyl substituted with one or more halogen, wherein the alkyl group is as herein described.

The term “halogen” means fluorine, chlorine, bromine, or iodine.

The term “heteroaryl” means an aromatic monocyclic or multi-cyclic ring system of about 5 to about 19 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In the case of multi-cyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as “heteroaryl”. Preferred heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen, carbon, or sulfur atom in the heteroaryl ring may be optionally oxidized; the nitrogen may optionally be quaternized. Representative heteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like.

As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to 18-membered ring (radical) which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocycle may be a monocyclic, or a polycyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycle may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the ring may be partially or fully saturated. Examples of such heterocycles include, without limitation, azepinyl, azocanyl, pyranyl dioxanyl, dithianyl, 1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Further heterocycles and heteroaryls are described in Katritzky et al., eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, N.Y. (1984), which is hereby incorporated by reference in its entirety.

The term “method of treating” means amelioration or relief from the symptoms and/or effects associated with the disorders described herein. As used herein, reference to “treatment” of a patient is intended to include prophylaxis.

The term “monocyclic” used herein indicates a molecular structure having one ring.

The term “optionally substituted” is used to indicate that a group may have a substituent at each substitutable atom of the group (including more than one substituent on a single atom), provided that the designated atom's normal valency is not exceeded and the identity of each substituent is independent of the others. In accordance with the present invention, up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy. “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., =0), then two hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term “pharmaceutical composition” means a composition comprising a compound of formula I and at least one component comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. As used herein, the term “pharmaceutically acceptable carrier” is used to mean any carrier, diluent, adjuvant, excipient, or vehicle, as described herein. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.

The term “pharmaceutically acceptable” means it is, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable dosage forms” means dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules, and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., latest edition, which is hereby incorporated by reference in its entirety.

The term “pharmaceutically acceptable prodrugs” as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” means compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Commonly, the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p. 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Design and Applications of Prodrugs,” p. 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgaard, 8, p. 1-38 (1992); Journal of Pharmaceutical Sciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692 (1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press (1987), which are incorporated herein by reference in their entirety. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.

The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N′dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine, and tris (hydroxymethyl) aminomethane; alkali metal salts, such as but not limited to lithium, potassium, and sodium; alkali earth metal salts, such as but not limited to barium, calcium, and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids. Pharmaceutical acceptable enol ethers include, but are not limited to, derivatives of formula C═C (OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C═C (OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. Pharmaceutical acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2,3 or 4, solvent or water molecules.

The term “polycyclic” or “multi-cyclic” used herein indicates a molecular structure having two or more rings, including, but not limited to, fused, bridged, or spiro rings.

Terminology related to “protecting”, “deprotecting,” and “protected” functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups.” Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1991), which is hereby incorporated by reference in its entirety.

The term “solvate” refers to a compound of formula I in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.

The term “therapeutically effective amount” is meant to describe an amount of compound of the present invention effective producing the desired therapeutic effect. Such amounts generally vary according to a number of factors well within the purview of ordinarily skilled artisans given the description provided herein to determine and account for. These include, without limitation: the particular subject, as well as its age, weight, height, general physical condition, and medical history, the particular compound used, as well as the carrier in which it is formulated and the route of administration selected for it; and, the nature and severity of the condition being treated.

Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (−)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

This invention also envisions the “quaternization” of any basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.

In the characterization of some of the substituents, it is recited that certain substituents may combine to form rings. Unless stated otherwise, it is intended that such rings may exhibit various degrees of unsaturation (from fully saturated to fully unsaturated), may include heteroatoms and may be substituted with lower alkyl or alkoxy.

In accordance with one embodiment of the present invention, compounds represented by formula I above may be substituted derivatives either of hexahydroazepino[4,3-b]indole, where G is —NR⁸—CH₂—CH₂—, of hexahydroazepino[4,5-b]indole, where G is —CH₂—NR⁸—CH₂—, or of hexahydroazepino[3,4-b]indole, where G is —CH₂—CH₂—NR⁸—.

In accordance with one embodiment of the present invention, R¹ is H. In accordance with another embodiment of the present invention, R¹ is optionally substituted C₁-C₆ alkyl, for example, methyl. In accordance with yet another embodiment of the present invention, R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl.

In accordance with one embodiment of the present invention, R²-R⁵ are each independently selected from the group consisting of H and optionally substituted C₁-C₆ alkyl.

In accordance with one embodiment of the present invention, R² and R³ or R⁴ and R⁵ combine to form an oxo group (carbonyl).

In accordance with one embodiment of the present invention, R⁶ is H, halogen, or optionally substituted C₁-C₆ alkyl.

In accordance with one embodiment of the present invention, R⁷ is H, halogen, or optionally substituted C₁-C₆ alkyl.

In accordance with one embodiment of the present invention, R⁸ is H. In accordance with another embodiment of the present invention, R⁸ is optionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, and 2-propyl.

In accordance with one embodiment of the present invention, X is N, CH, or CH₂.

In accordance with one embodiment of the present invention, Y is N, C, or CH.

In accordance with one embodiment of the present invention, L is a bond. In accordance with another embodiment of the present invention, L is —CH₂—O—.

In accordance with one embodiment of the present invention, B is aryl. In one preferred embodiment, B is phenyl. In accordance with another embodiment of the present invention, B is heteroaryl. In one preferred embodiment, B is pyridinyl, for example pyridin-2-yl or pyridin-3-yl, pyridazinyl, for example, pyridazin-3-yl, or pyrimidinyl, for example, pyrimidin-5-yl.

As described herein, B may be optionally substituted. In one preferred embodiment, B is unsubstituted. In another preferred embodiment, B is substituted with one substituent selected from trifluoromethyl, chloro, fluoro, methyl, and methanethio.

In accordance with one embodiment of the present invention, B is selected from the group consisting of phenyl, 4-(trifluoromethyl)phenyl, 4-(methylthio)-phenyl, 5-(trifluoromethyl)pyridin-2-yl, 2-(trifuloromethyl)-pyrimidin-5-yl, and 6-(trifluoromethyl)pyridazin-3-yl, 5-fluoro-pyridin-2-yl, 6-methylpyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 5-chloro-pyridin-2-yl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, 4-chloro-phenyl, 4-chloro-2-fluoro-phenyl, 3,5-dichloro-pyridin-2-yl, 4-fluoro-phenyl, pyridin-2-yl, and 3,5-difluoro-pyridin-2-yl.

Within these embodiments, the selection of a particular preferred substituent at any one of R¹-R¹⁸, X, Y, Z, L, A, and B does not affect the selection of a substituent at any of the others of R¹-R¹⁸, X, Y, Z, L, A, and B. That is, preferred compounds provided herein have any of the preferred substituents at any of the positions.

In accordance with one embodiment of the present invention, the compound has the structure:

In accordance with one embodiment of the present invention, the compound has the structure

wherein R¹⁹, R²⁰, and R²¹ are individually selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and —CN.

In accordance with another embodiment of the present invention, the compound has the structure

wherein R¹⁹, R²⁰, and R²¹ are individually selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and —CN.

In accordance with a further embodiment of the present invention, the compound has the structure

wherein R¹⁹, R²⁰, and R²¹ are individually selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and —CN.

In accordance with one embodiment of the present invention, the compound is selected from

In accordance with another embodiment of the present invention, the compound is selected from

In accordance with yet another embodiment of the present invention, the compound is selected from

Table 1, infra, lists compounds representative of embodiments of the present invention.

One embodiment of the present invention relates to pharmaceutically acceptable salts, or non-salt forms, of any of the compounds of formula I described herein. In one embodiment, the salt is a HCl salt.

Single enantiomers, any mixture of enantiomers, including racemic mixtures, or diastereomers (both separated and as any mixtures) of the compounds of the present invention are also included within the scope of the invention.

The scope of the present invention also encompasses active metabolites of the present compounds.

The present invention also includes compounds of formula I, wherein one or more of the atoms, e.g., C or H, are replaced by the corresponding radioactive isotopes of that atom (e.g., C replaced by ¹⁴C and H replaced by ³H), or a stable isotope of that atom (e.g., C replaced by ¹³C or H replaced by ²H). Radioisotopes of hydrogen, carbon, phosphorous, fluorine iodine and chlorine include ³H, ¹⁴C, ³⁵S, ¹⁸F, ³²P, ³³P, ¹²⁵I, and ³⁶Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Radiolabeled compounds described herein and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical to bind to neurotransmitter proteins. In addition, in the case of stable isotopes, such compounds may have the potential to favorably modify the biological properties, e.g., pharmacological and/or pharmacokinetic properties, of compounds of formula I. The details concerning selection of suitable sites for incorporating radioactive isotopes into the compounds are known to those skilled in the art.

Compounds of the present invention as described herein are useful as MCH-1 receptor antagonists. It may be found upon examination that compounds that are not presently excluded from the claims are not patentable to the inventors in this application. In that case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention. The invention, in a compound aspect, is all compounds of formula I, except those that are in the public's possession.

While it may be possible for compounds of formula I to be administered as the raw chemical, it will often be preferable to present them as part of a pharmaceutical composition. Accordingly, another aspect of the present invention is a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Furthermore, when reference is made in an independent claim to a compound or a pharmaceutically acceptable salt thereof, it will be understood that claims which depend from that independent claim which refer to such a compound also include pharmaceutically acceptable salts of the compound, even if explicit reference is not made to the salts.

Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents, or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.

In one embodiment of the present invention, the pharmaceutical composition further comprises one or more other therapeutic adjuncts, e.g., other compounds effective in the treatment of obesity, anxiety, depression, or non-alcoholic fatty liver disease, that are known to persons of skill in the art. Such other therapeutic adjuncts are described below.

Another aspect of the present invention relates to a method of treating a disease or condition which is susceptible to treatment with an MCH-1 receptor antagonist. This method involves selecting a patient with a disease or condition which is susceptible to treatment with an MCH-1 receptor antagonist and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Diseases or conditions which are susceptible to treatment with an MCH-1 receptor antagonist in accordance with the present invention include, but are not limited to, obesity, general anxiety disorders, social phobias, vertigo, obsessive-compulsive disorders, panic disorders, post-traumatic stress disorders, Parkinson's Disease Psychosis, schizophrenia, cognitive decline and defects in schizophrenia, Parkinson's Disease, Huntington's Chorea, presenile dementias, Alzheimer's Disease, psychological disorders, depression, substance abuse disorders, dementia associated with neurodegenerative disease, cognition deficits, and epilepsy (see PCT Publication No. WO 2007/010275, which is hereby incorporated by reference in its entirety).

As described above, the compounds of the present invention are useful as MCH-1 antagonists. As used in this invention, the term “antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist.

As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating diseases or disorders in which MCH-1 receptor activity is implicated.

In another embodiment of the present invention, the above method further involves administering a therapeutically effective amount of one or more therapeutic adjuncts. Suitable therapeutic adjuncts include, but are not limited to, anti-obesity and/or anorectic agents, anti-anxiety agents, anti-depression agents, and anti-non-alcoholic fatty liver disease agents.

Suitable anti-obesity and/or anorectic adjuncts include, but are not limited to, phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist or inverse agonist, a melanin concentrating hormone receptor antagonist, a serotonin 5-HT₆ receptor antagonist, a serotonin 5-HT_(2C) receptor agonist, the OB protein (hereinafter referred to as “leptin”), a leptin analog, a leptin receptor agonist, the amylin peptide, an amylin analog, an amylin receptor agonist, a neuropeptide Y receptor modulator, a galanin antagonist, or a GI lipase inhibitor or decreaser (such as orlistat). Other anorectic agents include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine.

Suitable anti-anxiety adjuncts include, but are not limited to, an allosteric modulator of the GABA_(A) receptor (such as diazepam, lorazepam, or alprazolam), a serotonin 5-HT_(1A) receptor partial agonist (such as buspirone), a selective serotonin reuptake inhibitor (SSRI, such as citalopram, escitalopram, fluoxetine, paroxetine, or sertraline), a serotonin-norepinephrine reuptake inhibitor (SNRI, such as duloxetine or venlafaxine), a monoamine neurotransmitter reuptake inhibitor of the tricyclic antidepressant (TCA) class (such as amitriptyline, desipramine, or imipramine), a combined serotonin reuptake inhibitor and 5-HT_(2C) antagonist (such as trazodone), and an H₁ receptor antagonist (such as hydroxyzine).

Suitable anti-depression adjuncts include, but are not limited to, a serotonin 5-HT_(1A) receptor partial agonist (such as buspirone), a selective serotonin reuptake inhibitor (SSRI, such as citalopram, escitalopram, fluoxetine, paroxetine, or sertraline), a serotonin-norepinephrine reuptake inhibitor (SNRI, such as duloxetine or venlafaxine), a monoamine neurotransmitter reuptake inhibitor of the tricyclic antidepressant (TCA) class (such as amitriptyline, desipramine, or imipramine), a combined serotonin reuptake inhibitor and 5-HT_(2C) antagonist (such as trazodone), a noradrenergic and specific serotonergic antidepressant (NaSSA, such as mianserin or mirtazapine), a norepinephrine reuptake inhibitor (NRI, such as atomoxetine or Mazindol), a norepinephrine-dopamine reuptake inhibitor (NDRI, such as bupropion), and a monoamine oxidase inhibitor (MAOI, such as isocarboxazid or moclobemide).

Suitable anti-non-alcoholic fatty liver disease adjuncts include, but are not limited to, an AMP-activated protein kinase (AMPK) agonist (such as metformin), a peroxisome proliferator-activated receptor (PPAR) gamma activator (such as rosiglitazone, pioglitazone, or troglitazone), a HMG-CoA reductase inhibitor (such as atorvastatin or simvastatin), and a PDE4 inhibitor (such as pentoxifylline).

In one embodiment, the patient is a mammal. The term “mammal” is used in its dictionary sense. The term “mammal” includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates, including humans.

The present invention also relates to a method of treating obesity in a subject in need of weight loss. This method involves selecting a patient in need of weight loss and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-obesity adjunct, as described above.

Yet another aspect of the present invention relates to a method of treating obesity in a subject who has experienced weight loss. This method involves selecting a patient who has experienced weight loss and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a method of treating anxiety. This method involves selecting a patient with anxiety and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-anxiety adjunct, as described above.

The present invention also relates to a method of treating depression. This method involves selecting a patient with depression and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-depression adjunct, as described above.

Another aspect of the present invention relates to a method of treating non-alcoholic fatty liver disease. This method involves selecting a patient who has non-alcoholic fatty liver disease and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-non-alcoholic fatty liver disease adjunct, as described above.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

The present invention also relates to a process for preparation of a product compound of formula I:

This process involves treating a first intermediate of formula II:

wherein Q is a halogen, under conditions effective to form the product compound of formula I, wherein R¹-R¹⁸, G, X, Y, Z, L, A, and B are as defined above.

In one embodiment, treating involves reacting the first intermediate with a second intermediate having the structure:

Compounds useful according to the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example, those described by Larock, Comprehensive Organic Transformations, Wiley-VCH publishers, New York (1989), which is hereby incorporated by reference in its entirety.

A compound of formula I including a group containing one or more nitrogen ring atoms, may be converted to the corresponding compound wherein one or more nitrogen ring atom of the group is oxidized to an N-oxide, preferably by reacting with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.

In the reactions described hereinafter, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice and as described above.

The novel MCH-1 antagonists of formula I of this invention can be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents, and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are known in the art but are not mentioned here. Although the syntheses depicted herein may result in the preparation of enantiomers having a particular stereochemistry, included within the scope of the present invention are compounds of formula I in any stereoisomeric form, and preparation of compounds of formula I in stereoisomeric forms other than those depicted herein would be obvious to one of ordinary skill in the chemical arts based on the procedures presented herein.

Synthetic Methods

Compounds of formula 3 (wherein R¹ is H or alkyl and R⁸ is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl) can be prepared from compounds of formula 1 (or a salt thereof, wherein R¹ is H or alkyl and Z is CH or N) and azepanone 2 (wherein R⁸ is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl) under heated acidic conditions. In the case where R¹ is H, optional alkylation or protection of compound 3 can provide compounds of formula 3 wherein R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl. Optional removal of protecting group R⁸ and reductive amination or alkylation can provide compounds of formula 3 wherein R⁸ is alkyl.

Compounds of formula 5 (wherein R¹ is H and Z is CH or N) can be prepared from compounds of formula 1 (or a salt thereof, wherein R¹ is H and Z is CH or N) and cyclohexanone 4 under heated acidic conditions. Treatment of compounds of formula 5 under with an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone can provide compounds of formula 6 (wherein R¹ is H and Z is CH or N). Optional N-alkylation or N-protection of compound 6 can provide compounds of formula 6 wherein R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl. Compounds of formula 6 can be converted to the corresponding oxime 7 and then heated under acidic conditions to provide compounds of formula 8 (wherein R¹ is H, alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl and Z is CH or N). Treatment of compounds of formula 8 with a reducing agent such as BH₃.THF under heated conditions can provide compounds of formula 9 wherein R⁸ is H. Optional reductive amination, alkylation, or protection can provide compounds of formula 9 wherein R⁸ is alkyl or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.

Alternatively, compounds of formula 5 can be treated with an oxidizing agent such as periodic acid to provide compounds of formula 10 (wherein R¹ is H and Z is CH or N). Optional N-alkylation or N-protection of compound 10 can provide compounds of formula 10 wherein R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl. Compounds of formula 10 can be converted to the corresponding oxime 11 and then heated under acidic conditions to provide compounds of formula 12(wherein R¹ is H, alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl and Z is CH or N). Treatment of compounds of formula 12 with a reducing agent such as BH₃.THF under heated conditions can provide compounds of formula 13 wherein R⁸ is H. Optional reductive amination, alkylation, or protection can provide compounds of formula 13 wherein R⁸ is alkyl or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.

Compounds of formula 17 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, S-alkyl, alkyl, halo, —CF₃, and —CN; A is CH; X is CH; and L is —CH₂—O— or a bond) can be prepared by treating compounds of formula 14 (wherein X¹ is chlorine, bromine or iodine; A is CH; and X is CH) with compounds of formula 15 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, —O-alkyl, alkyl, halo, —CF₃, and —CN; Z¹ is B(OH)₂, B(OR²²)₂, SnR²² ₃ or the like and R²² is alkyl), a catalyst such as palladium(0), and a base such as potassium carbonate to give compounds of formula 16, wherein L is a direct bond. Alternatively, in the case where Z¹ is —CH₂—OH and B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, compounds of formula 15 can be treated with a base such as sodium hydride and compounds of formula 14 under heated conditions to give compounds of formula 16, wherein L is —CH₂—O—. In turn, compounds of formula 16 can be treated with acetic anhydride under heated conditions followed by methanol and water or methanol and sodium hydroxide under ambient to heated conditions to provide compounds of formula 17, wherein L is —CH₂O— or a direct bond.

Alternatively, compounds of formula 17 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; A is CH or N; X is CH; and L is —CH₂—CH₂—, or a bond) can be prepared by treating compounds of formula 18 (wherein X¹ is chlorine, bromine or iodine; X² is —O—CH₃ or chlorine; A is CH or N; and X is CH) with compounds of formula 15 (wherein Z¹ is —CH═CH—B(OR²²)², B(OH)₂, B(OR²²)₂, SnR²² ₃ or the like and R²² is alkyl), a catalyst such as palladium(0), and a base such as potassium carbonate to give compounds of formula 19, wherein L is —CH═CH— or a direct bond, in accordance with Z¹. In the case where L is —CH═CH—, compounds of formula 19 can be treated with palladium on carbon under an atmosphere of hydrogen to give compounds of formula 19, wherein L is —CH₂CH₂—. Alternatively, in the case where Z¹ is —CH₂—OH, compounds of formula 18 can be treated with compounds of formula 15, a catalyst such as copper iodide, a ligand such as 3,4,7,8-tetramethylphenanthroline and a base such as cesium carbonate under heated conditions to give compounds of formula 19, wherein L is —CH₂—O—. In turn, when L is —CH₂—CH₂—, —CH₂—O— or a direct bond, compounds of formula 19 can be heated under acid conditions to provide compounds of formula 17, wherein L is —CH₂—CH₂—, —CH₂—O— or a direct bond, respectively.

Alternatively, compounds of formula 17 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, S-alkyl, alkyl, halo, —CF₃, and —CN; A is CH; X is N; and L is —CH₂—O— or a bond) can be prepared from compounds of formula 20 (wherein A is CH; X is N; and R²³ is a protecting group such as tetrahydropyran-2-yl). The hydroxyl group on compound 20 can be converted to an appropriate activating group to give compounds of formula 21. In the case where Z² is triflate, compounds of formula 20 can be treated with trifluoromethylsulfonic anhydride or N-phenyl trifluoromethanesulfonamide and a base such as triethylamine, pyridine or lithium bis(trimethylsilyl)amide under cooled conditions to give compounds of formula 21. Treatment of compounds of formula 21 with compounds of formula 15 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, S-alkyl, alkyl, halo, —CF₃, and —CN; Z¹ is B(OH)₂, B(OR²²)₂, SnR²² ₃ or the like, and R²² is alkyl), a catalyst such as palladium(0), and a base such as potassium carbonate under heated conditions can provide compounds of formula 22, wherein L is a direct bond. Alternatively, in the case where Z¹ is —CH₂—Br, compounds of formula 15 can be treated with compounds of formula 20 and a base such as as potassium carbonate to give compounds of formula 22, wherein L is —CH₂—O—. Removal of the protecting group R²³ on compound 22 can provide compounds of formula 17, wherein L is —CH₂—O— or a bond.

Compounds of formula 24 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; L is —CH₂—CH₂—, —CH₂—O— or a bond; A is CH or N; X is CH or N; Z is CH or N; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂— or —CH₂—CH₂—NR⁸—; R⁸ is H, alkyl, or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each H or, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to form a carbonyl oxygen) can be prepared by treating compounds of formula 23 (wherein Z is CH or N; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂—, or —CH₂—CH₂—NR⁸—, R⁸ is H, alkyl, or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each H or, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to form a carbonyl oxygen) under heated conditions with a catalyst such as copper iodide, a ligand such as trans-1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and compounds of formula 17 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; L is —CH₂—CH₂—, —CH₂—O— or a bond; A is CH or N; and X is CH or N). In the case where R⁸ is a protecting group, the protecting group can be removed to give compounds of formula 24 wherein R⁸ is H. In the case where R⁸ is H, reductive amination or alkylation can provide compounds of formula 24, wherein R⁸ is an alkyl group. Additionally, in the case where R¹ is a protecting group, the protecting group can be removed to give compounds of formula 24 wherein R¹ is H.

Compounds of formula 25 (wherein A is CH or N; X is CH or N; Z is CH or N; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂—, or —CH₂—CH₂—NR⁸—; R⁸ is H, alkyl, or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each H or, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to form a carbonyl oxygen) can be treated with hydrogen and a catalyst such as palladium on carbon to provide compounds of formula 26. The hydroxyl group on compounds of formula 26 can be converted to an appropriate activating group to give compounds of formula 27. In the case where Z² is triflate, compounds of formula 26 can be treated with trifluoromethylsulfonic anhydride or N-phenyl trifluoromethanesulfonamide and a base such as pyridine or lithium bis(trimethylsilyl)amide under cooled conditions to give compounds of formula 27. Treatment of compounds of formula 27 with compounds of formula 15 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, R²¹ are each independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; Z¹ is —CH═CH—B(OR²²)₂, B(OH)₂, B(OR²²)₂, SnR²² ₃ or the like and R²² is alkyl), a catalyst such as palladium(0), and a base such as potassium carbonate under heated conditions can provide compounds of formula 24, wherein L is —CH═CH— or a direct bond. In the case where L is —CH═CH—, compounds of formula 24 can be treated with palladium on carbon under an atmosphere of hydrogen to give compounds of formula 24, where L is —CH₂CH₂—.

Compounds of formula 29 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and L is —CH₂—CH₂—) can be prepared by treating piperazin-2-one 28 with compounds of formula 15 (wherein Z¹ is —CH₂—CH₂—X¹; and X¹ is a leaving group such as chlorine, bromine, iodine or the like) and a base such as di-isopropylamine to give compounds of formula 29, wherein L is —CH₂—CH₂—.

Compounds of formula 30 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; L is —CH₂—CH₂—; Z is CH or N; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂— or —CH₂—CH₂—NR⁸—; R⁸ is H, alkyl, or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each H or, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to form a carbonyl oxygen) can be prepared by treating compounds of formula 23 (wherein Z is CH or N; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂—, or —CH₂—CH₂—NR⁸—, R⁸ is H, alkyl, or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or a protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each H or, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to form a carbonyl oxygen) under heated conditions with a catalyst such as copper iodide, a ligand such as trans-1,2-bis(methylamino)cyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and compounds of formula 29 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and L is —CH₂—CH₂—). In the case where R⁸ is a protecting group, the protecting group can be removed to give compounds of formula 30 wherein R⁸ is H. In the case where R⁸ is H, reductive amination or alkylation can provide compounds of formula 30, wherein R⁸ is an alkyl group. Additionally, in the case where R¹ is a protecting group, the protecting group can be removed to give compounds of formula 30 wherein R¹ is H.

The present invention provides compositions containing the compounds described herein, including, in particular, pharmaceutical compositions comprising therapeutically effective amounts of the compounds and pharmaceutically acceptable carriers.

It is a further object of the present invention to provide kits having a plurality of active ingredients (with or without carrier) which, together, may be effectively utilized for carrying out the novel combination therapies of the invention.

It is another object of the invention to provide a novel pharmaceutical composition which is effective, in and of itself, for utilization in a beneficial combination therapy because it includes a plurality of active ingredients which may be utilized in accordance with the invention.

The present invention also provides kits or single packages combining one or more active ingredients useful in treating the disease. A kit may provide (alone or in combination with a pharmaceutically acceptable diluent or carrier) the compounds of formula I and an additional active ingredient (alone or in combination with diluent or carrier), as described above.

The products according to the present invention may be presented in forms permitting administration by the most suitable route and the invention also relates to pharmaceutical compositions containing at least one product according to the invention which are suitable for use in human or veterinary medicine. These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media, and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.

The formulations of compounds of formula I include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intraperitoneal, intravenous, and intraarticular), rectal, colonic, and topical (including dermal, buccal, nasal, sublingual, and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (“active ingredient”) with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed, or controlled release of the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceutically acceptable inert carrier”, and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, “Pharmaceutically acceptable carrier” also encompasses controlled release means.

Pharmaceutical compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must be compatible with the compound of formula I to insure the stability of the formulation. The composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.

Examples of excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, anti-microbial agents, and coating agents.

The dose range for adult humans is generally from 0.001 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formula I which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95% of the total composition.

A dosage unit (e.g. an oral dosage unit) can include from, for example, 0.01 to 0.1 mg, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 0.01 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described herein.

The products according to the present invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.

For additional information about pharmaceutical compositions and their formulation, see, for example, Remington, The Science and Practice of Pharmacy, 20^(th) Edition (2000), which is hereby incorporated by reference in its entirety.

The compounds of formula 1 can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasally (including using a cannula), or by other routes. The compounds of formula I can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g. PCT Publication No. WO 97/11682, which is hereby incorporated by reference in its entirety) via a liposomal formulation (see, e.g., European Patent EP 736299 and PCT Publication Nos. WO 99/59550 and WO 97/13500, which are hereby incorporated by reference in their entirety), via formulations described in PCT Publication No. WO 03/094886, which is hereby incorporated by reference in its entirety, or in some other form. The compounds of formula I can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al., Nature Reviews Drug Discovery 3:115 (2004), which is hereby incorporated by reference in its entirety)). The compounds can be administered locally, for example, at the site of injury to an injured blood vessel. The compounds can be coated on a stent. The compounds can be administered using high-velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. Patent Publication No. 20020061336, which is hereby incorporated by reference in its entirety. Additional particle formulations are described in PCT Publication Nos. WO 00/45792, WO 00/53160, and WO 02/19989, which are hereby incorporated by reference in their entirety. An example of a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can be found in PCT Publication No. WO 89/04179, which is hereby incorporated by reference in its entirety. PCT Publication No. WO 96/11705, which is hereby incorporated by reference in its entirety, provides formulations suitable for transdermal administration.

The compounds can be administered in the form a suppository or by other vaginal or rectal means. The compounds can be administered in a transmembrane formulation as described in PCT Publication No. WO 90/07923, which is hereby incorporated by reference in its entirety. The compounds can be administered non-invasively via the dehydrated particles described in U.S. Pat. No. 6,485,706, which is hereby incorporated by reference in its entirety. The compound can be administered in an enteric-coated drug formulation as described in PCT Publication No. WO 02/49621, which is hereby incorporated by reference in its entirety. The compounds can be administered intranasaly using the formulation described in U.S. Pat. No. 5,179,079, which is hereby incorporated by reference in its entirety. Formulations suitable for parenteral injection are described in PCT Publication No. WO 00/62759, which is hereby incorporated by reference in its entirety. The compounds can be administered using the casein formulation described in U.S. Patent Publication No. 20030206939 and PCT Publication No. WO 00/06108, which are hereby incorporated by reference in their entirety. The compounds can be administered using the particulate formulations described in U.S. Patent Application Publication No. 20020034536, which is hereby incorporated by reference in its entirety.

The compounds, alone or in combination with other suitable components, can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation. Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasal applications. Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like. Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion.

Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S. Pat. No. 6,524,557 and references therein, which is hereby incorporated by reference in its entirety. The surfactants described in U.S. Pat. No. 6,524,557, which is hereby incorporated by reference in its entirety, e.g., a C₈-C₁₆ fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.

Also suitable in the invention are dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-powder inhaler. Absorption enhancers that can be added to dry powder formulations of the present invention include those described in U.S. Pat. No. 6,632,456, which is hereby incorporated by reference in its entirety. PCT Publication No. WO 02/080884, which is hereby incorporated by reference in its entirety, describes new methods for the surface modification of powders. Aerosol formulations may include U.S. Pat. No. 5,230,884, U.S. Pat. No. 5,292,499, PCT Publication No. WO 017/8694, PCT Publication No. WO 01/78696, U.S. Patent Application Publication No. 2003019437, U.S. Patent Application Publication No. 20030165436, and PCT Publication No. WO 96/40089 (which includes vegetable oil), which are hereby incorporated by reference in their entirety. Sustained release formulations suitable for inhalation are described in U.S. Patent Application Publication Nos. 20010036481A1, 20030232019A1, and 20040018243A1 as well as in PCT Publication Nos. WO 01/13891, WO 02/067902, WO 03/072080, and WO 03/079885, which are hereby incorporated by reference in their entirety.

Pulmonary formulations containing microparticles are described in PCT Publication No. WO 03/015750, U.S. Patent Application Publication No. 20030008013, and PCT Publication No. WO 00/00176, which are hereby incorporated by reference in their entirety. Pulmonary formulations containing stable glassy state powder are described in U.S. Patent Application Publication No. 20020141945 and U.S. Pat. No. 6,309,671, which are hereby incorporated by reference in their entirety. Other aerosol formulations are described in EP 1338272A1, PCT Publication No. WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, PCT Publication No. WO 91/04011, and U.S. Pat. No. 6,294,153, which are hereby incorporated by reference in their entirety, and U.S. Pat. No. 6,290,987, which is hereby incorporated by reference in its entirety, describes a liposomal based formulation that can be administered via aerosol or other means.

Powder formulations for inhalation are described in U.S. Patent Application Publication No. 20030053960 and PCT Publication No. WO 01/60341, which are hereby incorporated by reference in their entirety. The compounds can be administered intranasally as described in U.S. Patent Application Publication No. 20010038824, which is hereby incorporated by reference in its entirety.

Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer. Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles. More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy, which are hereby incorporated by reference in their entirety.

Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington, which are hereby incorporated by reference in their entirety.

Compounds of formula I can be incorporated into a liposome to improve half-life. Compounds of formula I can also be conjugated to polyethylene glycol (PEG) chains. Methods for pegylation and additional formulations containing PEG-conjugates (i.e. PEG-based hydrogels, PEG modified liposomes) can be found in Harris et al., Nature Reviews Drug Discovery, 2:214-221 (2003) and the references therein, which are hereby incorporated by reference in their entirety. Compounds of formula I can also be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International, Raleigh, N.C.). Compounds of formula I can also be delivered using nanoemulsion formulations.

EXAMPLES

The Examples set forth below are for illustrative purposes only and are not intended to limit, in any way, the scope of the present invention.

Example 1 Analytical Methods and Materials

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers at 300, 400 or 500 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using either a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) or a mass Varian 1200L single quadrapole mass spectrometer (ESI). High performance liquid chromatograph (HPLC) analyses were obtained using a Luna C18(2) column (250×4.6 mm, Phenomenex) or a Gemini C18 column (250×4.6 mm, Phenomenex) with UV detection at 254 nm or 223 nm using a standard solvent gradient program (Method A, Method B or Method C).

Method A:

Time Flow (min) (mL/min) % A % B 0.0 1.0 90.0 10.0 20 1.0 10.0 90.0 30 1.0 10.0 90.0 A = Water with 0.05% Trifluoroacetic Acid B = Acetonitrile with 0.05% Trifluoroacetic Acid Method B:

Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0 2.0 20 1.0 2.0 98.0 25 1.0 2.0 98.0 A = Water with 0.025% Trifluoroacetic Acid B = Acetonitrile with 0.025% Trifluoroacetic Acid Method C:

Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0 2.0 20 1.0 10.0 90.0 30 1.0 10.0 90.0 A = Water with 0.025% Trifluoroacetic Acid B = Acetonitrile with 0.025% Trifluoroacetic Acid

Example 2 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one dihydrochloride

a) tert-Butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A solution of 3-bromophenylhydrazine hydrochloride (8.070 g, 36.03 mmol) and tert-butyl 4-oxoazepane-1-carboxylate (7.710 g, 36.03 mmol) in 15:2 EtOH/(12 N HCl solution) (68 mL) was stirred at reflux for 28 h. The solution was concentrated under reduced pressure to afford a residue. Boc₂O (23.56 g, 108.1 mmol) was added to a suspension of the residue and K₂CO₃ (14.92 g, 108.1 mmol) in 1:1 H₂O/i-PrOH (180 mL) and the resulting suspension was stirred at 25° C. for 3 h. H₂O was added and the resulting suspension was filtered. The filtrate was extracted with CH₂Cl₂ and the combined extracts were dried over Na₂SO₄. The resulting solution was concentrated under reduced pressure and flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded 7.26 g of viscous oil. NaH (60% dispersion in oil, 1.59 g, 39.8 mmol) was added to a solution of the viscous oil in DMF (40 mL) under N₂ and the resulting suspension was stirred at 25° C. for 30 min. MeI (1.86 mL, 29.8 mmol) was added to the suspension and the resulting suspension was stirred at 25° C. for 1 h. H₂O was added and the aqueous solution was extracted with CH₂Cl₂. The combined extracts were washed with brine and dried over Na₂SO₄. The resulting solution was concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (2.71 g, 20%) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ 7.38 (br s, 1H), 7.34-7.24 (m, 1H), 7.17 (dd, J=8.4, 1.5 Hz, 1H), 3.70-3.57 (m, 7H), 3.04-2.91 (m, 4H), 1.48 (s, 9H).

b) 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (CAS Registry Number 1173155-65-1) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749 mmol), K₂CO₃ (310 mg, 2.25 mmol) and PdCl₂(dppf) (61 mg, 0.075 mmol) were stirred in DMSO (4 mL). The reaction mixture was degassed, then back-filled with N₂. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH₂Cl₂. The organic layer was washed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (115 mg, 60%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).

c) 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2 (1H)-one (CAS Registry Number 1173155-66-2) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115 mg, 0.451 mmol) was stirred in concentrated hydrochloric acid (20 mL) at 120° C. for 18 h and then concentrated. The residue was adjusted to pH 8 with 6 N NaOH and the solids were filtered off, washed with water and dried under vacuum to provide the title compound (120 mg, quant) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.61 (d, J=8.9 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 7.62 (d, J=6.8 Hz, 1H), 7.19 (s, 1H), 7.01 (dd, J=6.8, 1.6 Hz, 1H).

d) tert-Butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1 (2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (106 mg, 0.438 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (183 mg, 0.482 mmol), CuI (100 mg, 0.526 mmol), 8-hydroxyquinoline (13 mg, 0.09 mmol) and Cs₂CO₃ (157 mg, 0.482 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded the title compound (74 mg, 30%) as a viscous oil: ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.65 (d, J=6.9 Hz, 1H), 7.62-7.53 (m, 1H), 7.33 (br s, 1H), 7.30-7.21 (overlapping with solvent peak, 2H), 7.08 (d, J=8.1 Hz, 1H), 3.71-3.62 (m, 7H), 3.11-2.98 (m, 4H), 1.49 (s, 9H).

e) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluormethyl)pyridazin-3-yl)pyridin-2(1H)-one dihydrochloride

TFA (1 ml) was added to a solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (70 mg, 0.13 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirred for 1 h at 25° C. Saturated NaHCO₃ solution was added, and the phases were separated. The aqueous phase was extracted with CH₂Cl₂, and the combined organic extracts were dried over Na₂SO₄. The resulting solution was concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 39 mg of a yellow solid. 2 N HCl in Et₂O (0.07 mL, 0.14 mmol) was added to a solution of the yellow solid in CH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirred at 25° C. for 30 min. The solution was concentrated under reduced pressure to afford the title compound (39.5 mg, 59%) as a yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (br s, 2H), 8.70 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 7.90 (d, J=7.0 Hz, 1H), 7.62-7.59 (m, 2H), 7.38 (s, 1H), 7.17 (d, J=6.5 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 3.72 (s, 3H), 3.43-3.30 (m, 4H), 3.28-3.25 (m, 2H), 3.17-3.11 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 3 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride

a) 2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (CAS Registry Number 1108184-24-2) (WO 2009/015037 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol) were reacted according to Example 2 (step b) to provide the title compound (337 mg, 62%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).

b) 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (CAS Registry Number 1108184-25-3) (WO 2009/015037 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (337 mg, 1.32 mmol) was reacted reacted according to Example 2 (step c) to provide the title compound (289 mg, 89%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H) 9.10 (s, 1H), 8.35 (dd, J=8.4, 2.1 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.53 (d, J=6.8, 1H), 7.09 (d, J=1.3 Hz, 1H), 6.90 (dd, J=6.8, 1.6 Hz, 1H).

c) tert-Butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (178 mg, 0.740 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (255 mg, 0.673 mmol), CuI (154 mg, 0.808 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol) and Cs₂CO₃ (241 mg, 0.740 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135° C. for 36 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH was added and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded the title compound (133 mg, 33%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.00 (br s, 1H), 8.07 (br d, J=8.3 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.60-7.52 (m, 2H), 7.32 (s, 1H), 7.28-7.20 (overlapping with solvent peak, 1H), 7.11-7.02 (m, 2H), 3.84-3.60 (m, 7H), 3.12-2.95 (m, 4H), 1.49 (s, 9H).

d) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride

TFA (1 ml) was added to a solution of tert-butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (133 mg, 0.247 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirred for 1 h at 25° C. Saturated NaHCO₃ solution was added, and the phases were separated. The aqueous phase was extracted with CH₂Cl₂, and the combined organic extracts were dried over Na₂SO₄. The resulting solution was concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 39 mg of a yellow solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded 10 mg of a yellow solid. 2 N HCl in Et₂O (0.02 mL, 0.04 mmol) was added to a solution of the yellow solid in CH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirred at 25° C. for 30 min. The solution was concentrated under reduced pressure to afford the title compound (12 mg, 9%) as a yellow powder: mp 310-312° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.00 (br s, 2H), 8.40 (d, J=8.5 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.83 (d, J=7.0 Hz, 1H), 7.61-7.56 (m, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.08-7.05 (m, 2H), 3.72 (s, 3H), 3.43-3.23 (m, 6H), 3.16-3.11 (m, 2H); ESI MS m/z 439 [M+H]⁺.

Example 4 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one dihydrochloride

a) 2′-Methoxy-6-(trifluoromethyl)-3,4′-bipyridine (CAS Registry Number 1173155-80-0) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.24 g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g, 11 mmol) were reacted according to the procedure of Example 2 (step b) to provide the title compound (1.1 g, 81%) as a white solid: ESI MS m/z 255 [M+H].

b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (CAS Registry Number 1173155-81-1) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2′-Methoxy-6-(trifluoromethyl)-3,4′-bipyridine (1.1 g, 4.3 mmol) was reacted according to the procedure of Example 2 (step c) to provide the title compound (522 mg, 50%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.8 (br s, 1H), 9.10 (s, 1H), 8.40 (dd, J=8.1, 1.2 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.56 (d, J=6.7 Hz, 1H), 6.81 (s, 1H), 6.63 (dd, J=6.7, 1.3 Hz, 1H).

c) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one dihydrochloride

A suspension of 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (67 mg, 0.28 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (116 mg, 0.307 mmol), CuI (64 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg, 0.06 mmol) and Cs₂CO₃ (100 mg, 0.307 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 101 mg of a yellow solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded 70 mg of a viscous oil. 2 N HCl in Et₂O (100 mL) was added to a solution of the viscous oil in 1:1 CH₂Cl₂/MeOH (2 mL) under N₂ and the resulting suspension was stirred at 25° C. for 19 h. The suspension was filtered, and the solid was washed with CH₂Cl₂. The solid was washed with 9:1 CH₂Cl₂/MeOH and the resulting 9:1 CH₂Cl₂/MeOH solution was concentrated under reduced pressure to afford the title compound (35 mg, 25%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (d, J=1.5 Hz, 1H), 9.15-9.02 (m, 2H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.84 (d, J=7.3 Hz, 1H), 7.60-7.53 (m, 2H), 7.06 (dd, J=8.5, 1.5 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.80 (dd, J=7.3, 2.0 Hz, 1H), 3.72 (s, 3H), 3.42-3.37 (m, 2H), 3.36-3.24 (m, 4H), 3.16-3.12 (m, 2H); ESI MS m/z 439 [M+H]⁺.

Example 5 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one dihydrochloride

a) 2-Methoxy-4((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (CAS Registry Number 1173155-95-7) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

4-Bromo-2-methoxypyridine (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs₂CO₃ (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromagraphy (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: ¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).

b) 4((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (CAS Registry Number 1173155-96-8) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (3.19 g, 11.2 mmol) was reacted according to the procedure of Example 2 (step c) to provide the title compound (2.04 g, 67%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.2 (br s, 1H), 8.84 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.3, 2.5 Hz, 1H), 5.82 (d, J=2.4 Hz, 1H), 5.25 (s, 2H).

c) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one dihydrochloride

A suspension of 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (147 mg, 0.544 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (226 mg, 0.598 mmol), CuI (124 mg, 0.653 mmol), 8-hydroxyquinoline (16 mg, 0.11 mmol) and Cs₂CO₃ (195 mg, 0.598 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a brown solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded 95 mg of a yellow powder. 2 N HCl in Et₂O (200 mL) was added to a solution of the yellow powder in 1:1 CH₂Cl₂/MeOH (4 mL) under N₂ and the resulting suspension was stirred at 25° C. for 18 h. The suspension was filtered and the solid was washed with Et₂O to afford the title compound (80 mg, 27%) as a yellow solid: mp 296-300° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (br s, 2H), 8.89 (s, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 6.95 (d, (d, J=8.0 Hz, 1H), 6.14 (d, J=7.5 Hz, 1H), 6.01 (s, 1H), 5.35 (s, 2H), 3.69 (s, 3H), 3.41-3.29 (m, 4H), 3.28-3.22 (m, 2H), 3.14-3.10 (m, 2H); ESI MS m/z 469 [M+H]⁺.

Example 6 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one dihydrochloride

a) 5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (CAS Registry Number 1173155-89-9) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 13 mmol) were reacted according to the procedure of Example 2 (step b) to provide the title compound (1.0 g, 46%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 9.10 (s, 2H), 8.35 (d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 4.02 (s, 3H).

b) 4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(111)-one (CAS Registry Number 1173155-90-2) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (900 mg, 3.5 mmol) was reacted according to the procedure of Example 2 (step c) to provide the title compound (470 mg, 56%) as an orange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.6 (br s, 1H), 9.41 (s, 2H), 7.61 (d, J=6.8 Hz, 1H), 6.91 (s, 1H), 6.68 (dd, J=6.8, 1H).

c) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one dihydrochloride

A suspension of 4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (95 mg, 0.39 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (124 mg, 0.327 mmol), CuI (75 mg, 0.39 mmol), 8-hydroxyquinoline (9 mg, 0.07 mmol) and Cs₂CO₃ (117 mg, 0.360 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a green solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded 40 mg of a yellow powder. 2 N HCl in Et₂O (100 mL) was added to a solution of the yellow powder in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂, and the resulting suspension was stirred at 25° C. for 18 h. The suspension was filtered, and the solid was washed with Et₂O to afford the title compound (32 mg, 16%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 9.10 (br s, 2H), 7.89 (d, J=7.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.12 (s, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.86 (d, J=7.0 Hz, 1H), 3.72 (s, 3H), 3.42-3.33 (m, 4H), 3.29-3.24 (m, 2H), 3.16-3.12 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 7 Preparation of 4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A solution of 3-bromophenylhydrazine hydrochloride (10.39 g, 46.38 mmol) and tert-butyl 4-oxoazepane-1-carboxylate (9.927 g, 46.38 mmol) in 15:2 EtOH/(concentrated HCl solution) (68 mL) was stirred at reflux for 18 h. The solution was concentrated under reduced pressure to afford a residue. Boc₂O (30.33 g, 139.1 mmol) was added to a suspension of the residue and K₂CO₃ (19.20 g, 139.1 mmol) in 1:1 H₂O/i-PrOH (180 mL), and the resulting suspension was stirred at 25° C. for 1.5 h. H₂O was added and the resulting suspension was filtered. The filtrate was extracted with CH₂Cl₂, and the combined extracts were dried over Na₂SO₄. The resulting solution was concentrated under reduced pressure, and flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded 6.73 g of an amorphous solid. TsCl (4.21 g, 22.1 mmol) was added to a biphasic system of the amorphous solid and (Bu₄NH)₂SO₄ (50% weight solution in H₂O, 1.5 mL) in 5:3 toluene/(6 N NaOH in H₂O) (240 mL), and the resulting biphasic system was stirred at 25° C. for 1 h. The phases were separated. The organic phase was washed with H₂O, dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (3.78 g, 16%) as a yellow foam: ¹H NMR (300 MHz, CDCl₃) δ 8.45-8.39 (m, 1H), 7.63-7.54 (m, 2H), 7.37 (dd, J=8.4, 1.8 Hz, 1H), 7.30-7.18 (m, 3H), 3.69-3.51 (m, 4H), 3.35-3.27 (m, 2H), 2.90-2.79 (m, 2H), 2.37 (s, 3H), 1.45 (s, 9H).

b) 4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(benzyloxy)pyridin-2(1H)-one (71 mg, 0.35 mmol), tert-butyl 8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (202 mg, 0.389 mmol), CuI (81 mg, 0.43 mmol), 8-hydroxyquinoline (62 mg, 0.43 mmol) and Cs₂CO₃ (127 mg, 0.389 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 4.5 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 190 mg of a yellow solid. NaOH (594 mg, 14.8 mmol) was added to a solution of the yellow solid in 1:1 MeOH/CH₂Cl₂ (20 mL) under N₂, and the resulting suspension was stirred at reflux for 16 h. The reaction was cooled, H₂O was added, and the resulting suspension was filtered. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a green solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded 50 mg of a white powder. 2 N HCl in Et₂O (200 mL) was added to a solution of the white powder in 1:1 CH₂Cl₂/MeOH (4 mL) under N₂, and the resulting suspension was stirred at 25° C. for 18 h. The suspension was filtered, and the solid was washed with Et₂O to afford the title compound (35 mg, 23%) as a white solid: mp 258-260° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.06 (br s, 2H), 7.57-7.35 (m, 7H), 7.25 (s, 1H), 6.90 (d, J=8.0 Hz), 6.11-6.07 (m, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 3.45-3.30 (m, 4H), 3.20-3.15 (m, 2H), 3.12-3.06 (m, 2H); ESI MS m/z 386 [M+H]⁺.

Example 8 Preparation of 1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one dihydrochloride

a) tert-Butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (78 mg, 0.32 mmol), tert-butyl 8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (183 mg, 0.353 mmol), CuI (73 mg, 0.39 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs₂CO₃ (115 mg, 0.353 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded the title compound (95 mg, 44%) as a yellow viscous oil: ¹H NMR (300 MHz, CDCl₃) δ 8.35 (br s, 1H), 8.12 (d, J=8.9 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.71-7.63 (m, 4H), 7.54-7.47 (m, 1H), 7.39-7.22 (m, 4H), 3.73-3.58 (m, 4H), 3.44-3.31 (m, 2H), 2.95-2.86 (m, 2H), 2.37 (s, 3H), 1.47 (s, 9H).

b) 1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2 (1H)-one dihydrochloride

NaOH (293 mg, 7.33 mmol) was added to a solution of tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (100 mg, 0.147 mmol) in 1:1 MeOH/CH₂Cl₂ (20 mL) under N₂ and the resulting suspension was stirred at reflux for 19 h. The reaction was cooled, H₂O was added, and the resulting suspension was filtered. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 35 mg of a yellow solid. 2 N HCl in Et₂O (200 mL) was added to a solution of the white powder in 1:1 CH₂Cl₂/MeOH (4 mL) under N₂, and the resulting suspension was stirred at 25° C. for 18 h. The suspension was filtered, and the solid was washed with Et₂O to afford the title compound (18.6 mg, 25%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.27 (s, 1H), 9.09 (br s, 2H), 8.69 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.16 (d, J=7.3 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 3.41-3.25 (m, 4H), 3.23-3.17 (m, 2H), 3.14-3.09 (m, 2H); ESI MS m/z 426 [M+H]⁻.

Example 9 Preparation of 1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride

A suspension of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (109 mg, 0.454 mmol), tert-butyl 8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (259 mg, 0.500 mmol), CuI (104 mg, 0.545 mmol), 8-hydroxyquinoline (13 mg, 0.09 mmol) and Cs₂CO₃ (163 mg, 0.500 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 15 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 120 mg of a yellow solid. NaOH (353 mg, 8.82 mmol) was added to a solution of the yellow solid in 1:1 MeOH/CH₂Cl₂ (20 mL) under N₂, and the resulting suspension was stirred at reflux for 16 h. The reaction was cooled, H₂O was added, and the phases were separated. The organic phase was extracted with CH₂Cl₂. The combined extracts were dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 91 mg of a yellow solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the yellow solid in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂, and the resulting suspension was stirred at 25° C. for 18 h. The suspension was filtered, and the solid was washed with Et₂O and CH₂Cl₂ to afford the title compound (75 mg, 33%) as a orange solid: mp 288-290° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.26 (br s, 1H), 9.15 (br s, 1H), 9.08-9.00 (m, 2H), 8.40-8.32 (m, 2H), 7.81 (d, J=7.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.08-7.01 (m, 2H), 3.41-3.29 (m, 4H), 3.21-3.14 (m, 2H), 3.13-3.07 (m, 2H); ESI MS m/z 425 [M+H]⁺.

Example 10 Preparation of 5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridazin-3(2H)-one dihydrochloride

a) 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (CAS Registry Number 1008517-74-5) (WO 2008/022979 to Stenkamp et al., which is hereby incorporated by reference in its entirety)

This compound was prepared in accordance with the procedure of Stenkamp, et al., WO 2008022979, which is hereby incorporated by reference in its entirety.

b) 5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (CAS Registry Number 1008518-11-3) (WO 2008/022979 to Stenkamp et al., which is hereby incorporated by reference in its entirety)

5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.62 g, 13.4 mmol), 2-(bromomethyl)-5-fluoropyridine (7.6 g, 40 mmol) and K₂CO₃ (9.2 g, 67 mmol) were stirred in DMF (40 ml) and CH₂Cl₂ (40 ml) for 48 h. The mixture was diluted with CH₂Cl₂, was washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (1.1 g, 27%) as a light brown solid: ¹H NMR (300 MHz, CDCl₃) δ 8.47 (s, 1H), 7.73 (d, J=2.9 Hz, 1H), 7.47-7.43 (m, 2H), 6.19 (d, J=2.9 Hz, 1H), 6.03-5.98 (dd, J=10.7, 2.0 Hz, 1H), 5.12 (s, 2H), 4.18-4.08 (m, 1H), 3.78-3.69 (td, J=11.6, 2.6 Hz, 1H), 2.21-2.00 (m, 2H), 1.75-1.60 (m, 4H).

c) 5-((5-Fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (CAS Registry Number 1008518-42-4) (WO 2008/022979 to Stenkamp et al., which is hereby incorporated by reference in its entirety)

5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.1 g, 3.6 mmol) was stirred in MeOH (5 mL), and 2 N HCl in Et₂O (20 mL) was added. After 16 h, the mixture was diluted with Et₂O (100 mL) and the solid filtered off. The solid was stirred in NaHCO₃ solution (15 mL) for 15 minutes and then refiltered to provide the title compound (620 mg, 78%) as a pink solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.69 (s, 1H), 8.60 (d, J=2.8 Hz, 1H), 7.85-7.78 (td, J=8.7, 2.9 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.67-7.63 (dd, J=8.6, 4.5 Hz, 1H), 6.31 (s, 1H), 5.25 (s, 2H).

d) 5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridazin-3(2H)-one dihydrochloride

A suspension of 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (110 mg, 0.500 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (208 mg, 0.550 mmol), CuI (209 mg, 1.10 mmol), 8-hydroxyquinoline (15 mg, 0.100 mmol) and Cs₂CO₃ (179 mg, 0.550 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. overnight. The suspension was cooled and diluted with CH₂Cl₂. The resulting solution was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. The solid was triturated with MeOH and dried under reduced pressure to afford a white solid. 2 N HCl in Et₂O (200 mL) was added to a solution of the white solid in 1:1 CH₂Cl₂/MeOH (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 18 h. The suspension was filtered, and the solid was washed with Et₂O to afford the title compound (22 mg, 9%) as a white solid: mp 250-254° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.10-8.92 (m, 2H), 8.64 (d, J=2.5 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.85 (ddd, J=8.5, 8.5, 3.0 Hz, 1H), 7.71 (dd, J=8.5, 4.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.08 (dd, J=8.0, 2.0 Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 5.29 (s, 2H), 3.69 (s, 3H), 3.42-3.32 (m, 4H), 3.27-3.22 (m, 2H), 3.14-3.10 (m, 2H); ESI MS m/z 420 [M+H]⁺.

Example 11 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-one dihydrochloride

a) 2′-Methoxy-6-methyl-3,4′-bipyridine (CAS Registry Number 1173156-60-9) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g, 16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol) were reacted according to Example 2 (step b) to provide the title compound (2.1 g, 98%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, J=2.1 Hz, 1H), 8.23 (d, J=5.4 Hz, 1H), 7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1, 1H), 7.08 (dd, J=5.4, 1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H), 2.61 (s, 3H).

b) 4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (CAS Registry Number 1173156-63-2) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

2′-Methoxy-6-methyl-3,4′-bipyridine (2.1 g, 10.4 mmol) was reacted according to Example 2 (step c) to provide the title compound (1.36 mg, 68%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.65 (s, 1H) 8.78 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.1, 2.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 1H), 7.36 (d, J=8.1, 1H), 6.66 (d, J=1.4 Hz, 1H), 6.55 (dd, J=6.9, 1.8 Hz, 1H), 2.51 (s, 3H).

c) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-one dihydrochloride

A suspension of 4-(6-methylpyridin-3-yl)pyridin-2(1H)-one (96 mg, 0.52 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (235 mg, 0.619 mmol), CuI (118 mg, 0.619 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and Cs₂CO₃ (185 mg, 0.568 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂, and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 24 h. The suspension was passed through a plug of silica gel, and activated carbon was added to the filtrate. The suspension was filtered through Celite, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded an off-white solid. 1.25 N HCl in MeOH (5 mL) was added to the off-white solid under N₂, and the resulting suspension was stirred at 25° C. for 20 h. The suspension was concentrated under reduced pressure to afford the title compound (118 mg, 50%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (br s, 2H), 9.03 (s, 1H), 8.47-8.40 (m, 1H), 7.81 (d, J=7.0 Hz, 1H), 7.71-7.64 (m, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.04 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (br s, 1H), 6.78 (dd, J=7.0, 2.0 Hz, 1H), 3.71 (s, 3H), 3.41-3.31 (m, 4H), 3.29-3.25 (m, 2H), 3.17-3.12 (m, 2H), 2.66 (s, 3H); ESI MS m/z 385 [M+H]⁺.

Example 12 Preparation of 1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochloride

a) Di-tert-butyl 8-bromo-1,2,4,5-tetrahydroazepino[4,5-b]indole-3,6-dicarboxylate

A solution of 3-bromophenylhydrazine hydrochloride (15.75 g, 70.33 mmol) and tert-butyl 4-oxoazepane-1-carboxylate (15.05 g, 70.33 mmol) in 15:2 EtOH/(12 N HCl solution) (102 mL) was stirred at reflux overnight. The solution was concentrated under reduced pressure to afford a red oil. Boc₂O (46.00 g, 211.0 mmol) was added to a suspension of the red oil and K₂CO₃ (29.12 g, 211.0 mmol) in 1:1 H₂O/i-PrOH (180 mL), and the resulting suspension was stirred at 25° C. for 2 h. H₂O was added, and the resulting suspension was filtered. The filtrate was extracted with CH₂Cl₂, and the combined extracts were dried over Na₂SO₄. The resulting solution was concentrated under reduced pressure, and flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a viscous red oil. NaH (60% dispersion in oil, 5.626 g, 140.7 mmol) was added to a solution of the viscous red oil in DMF (60 mL) under N₂, and the resulting suspension was stirred at 25° C. for 45 min. MeI (6.6 mL, 106 mmol) was added to the suspension, and the resulting suspension was stirred at 25° C. for 2 h. H₂O was added, and the aqueous solution was extracted with CH₂Cl₂. The combined extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (1.62 g, 6%) as a yellow foam and the title compound (2.80 g, 9%) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ 8.28 (br s, 0.5H), 8.21 (br s, 0.5H), 7.34 (dd, J=8.4, 1.5 Hz, 1H), 7.30-7.22 (1H, overlapping with solvent), 3.85-3.63 (m, 4H), 3.39-3.32 (m, 2H), 2.99-2.91 (m, 2H), 1.68 (s, 4.5H), 1.67 (s, 4.5H), 1.48 (s, 9H).

b) 4-(4-(Trifluoromethyl)phenyl)pyridine 1-oxide (CAS Registry Number 545396-52-9) (WO 2003/049702 to Bo et al., which is hereby incorporated by reference in its entirety)

4-Chloropyridine-N-oxide (3.0 g, 23 mmol), 4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K₂CO₃ (4.8 g, 35 mmol) and PdCl₂(dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The flask was flushed with nitrogen, and the mixture was heated to 80° C. for 10 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]⁺.

c) 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (CAS Registry Number 942947-10-6) (U.S. Published Patent Application No. 2007/149513 to Chen et al., which is hereby incorporated by reference in its entirety)

4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9 mmol) was heated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15 mL). The resulting black solution was concentrated to a volume of 15 mL, and the solid was filtered off, rinsed with CH₂Cl₂ and dried under vacuum to provide the title compound (1.26 g, 66%) as a brown solid: ¹H NMR (300 MHz, CD₃OD) δ 7.80-7.74 (br m, 5H), 6.85-6.66 (br m, 2H).

d) 1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoro-methyl)phenyl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (219 mg, 0.915 mmol), di-tert-butyl 8-bromo-1,2,4,5-tetrahydroazepino[4,5-b]indole-3,6-dicarboxylate (467 mg, 1.01 mmol), CuI (261 mg, 1.37 mmol), 8-hydroxyquinoline (27 mg, 0.18 mmol) and Cs₂CO₃ (329 mg, 1.01 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 316 mg of a brown solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded 240 mg of a yellow solid. 2 N HCl in Et₂O (200 mL) was added to a solution of the yellow solid in 1:1 CH₂Cl₂/MeOH (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 19 h. The suspension was filtered, and the solid was washed with CH₂Cl₂ and Et₂O to afford the title compound (148 mg, 25%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.25 (s, 1H), 9.15 (br s, 2H), 8.00 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.70 (dd, J=7.0, 2.0 Hz, 1H), 3.40-3.31 (m, 4H), 3.26-3.18 (m, 2H), 3.09-3.14 (m, 2H); ESI MS m/z 424 [M+H]⁺.

Example 13 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one dihydrochloride

a) 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (CAS Registry Number 1173155-63-9) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) was dissolved in DMF (20 mL), and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) was added, and the reaction mixture was heated for 1 h at 120° C. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried and concentrated. Purification by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) provided the title compound (1.76 g, 50%) as a tan solid: ¹H NMR (300 MHz, CDCl₃) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).

b) 4-((5-Fluoroyridin-2-yl)methoxy)pyridin-2(1H)-one (CAS Registry Number 924311-90-0) (WO 2007/018248 to Ando et al., which is hereby incorporated by reference in its entirety)

4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol) was reacted according to Example 12 (step c) to provide the title compound (1.29 g, 73%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (s, 1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (dt, J=8.7, 2.9 Hz, 1H), 7.60 (dd, J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4, 2.6 Hz, 1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).

c) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one dihydrochloride

A suspension of 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (102 mg, 0.464 mmol), tert-butyl 8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (265 mg, 0.510 mmol), CuI (106 mg, 0.557 mmol), 8-hydroxyquinoline (13 mg, 0.093 mmol) and Cs₂CO₃ (166 mg, 0.510 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 172 mg of a yellow solid. NaOH (522 mg, 13.8 mmol) was added to a solution of the yellow solid in 1:1 MeOH/CH₂Cl₂ (20 mL) under N₂, and the resulting suspension was stirred at reflux for 18 h. The reaction was cooled, H₂O was added, and the resulting solution was extracted with CH₂Cl₂. The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. 2 N HCl in Et₂O (200 mL) was added to a solution of the white solid in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂, and the resulting suspension was stirred at 25° C. for 4 h. The suspension was filtered, and the solid was washed with Et₂O to afford the title compound (47 mg, 21%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.11 (br s, 2H), 8.62 (d, J=3.0 Hz, 1H), 7.83 (ddd, J=9.0, 9.0, 3.0 Hz, 1H), 7.65 (dd, J=9.0, 5.0 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 6.90 (dd, J=8.0, 2.0 Hz, 1H), 6.11 (d, J=8.0, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 3.38-3.29 (m, 4H), 3.20-3.16 (s, 2H), 3.11-3.07 (m, 2H); ESI MS m/z 405 [M+H]⁺.

Example 14 Preparation of 4-(Benzyloxy)-1-(3-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

2-Picoline borane (72 mg, 0.68 mmol) was added to a solution of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (98 mg, 0.23 mmol) and ethanal (0.04 mL, 1 mmol) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at 25° C. for 1 h. A second aliquot of ethanal (0.04 mL, 1 mmol) was added to the solution, and the resulting solution was stirred at 25° C. for 7 h. H₂O was added to the solution, and the resulting biphasic system was neutralized with saturated NaHCO₃ solution. CH₂Cl₂ was added to the biphasic system, and the phases were separated. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded an off-white solid. 2 N HCl in Et₂O (0.07 mL, 0.07 mmol) was added to a solution of the off-white solid in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂, and the resulting solution was stirred at 25° C. for 30 min. The solution was diluted with Et₂O, and the resulting suspension was filtered to afford the title compound (41 mg, 38%) as a white powder: mp 246-248° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (br s, 1H), 7.59-7.35 (m, 8H), 6.95 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 6.01-5.96 (m, 1H), 5.15 (s, 2H), 3.76-3.05 (m, 13H), 1.31 (t, J=7.0 Hz, 3H); ESI MS m/z 428 [M+H]⁺.

Example 15 Preparation of 4-(Benzyloxy)-1-(3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

2-Picoline borane (84 mg, 0.78 mmol) was added to a solution of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (98 mg, 0.23 mmol) and acetone (1 mL) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at reflux for 48 h. The solution was cooled and adjusted to pH 7 with saturated NaHCO₃ solution. The resulting solution was diluted with CH₂Cl₂. The phases were separated, and the organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded an off-white solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded 30 mg of a white powder. 2 N HCl in Et₂O (0.04 mL, 0.08 mmol) was added to a solution of the white powder in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂ and the resulting solution was stirred at 25° C. for 30 min. The solution was diluted with Et₂O and the resulting suspension was filtered to afford the title compound (23 mg, 20%) as a white powder: mp 256-258° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.89 (br s, 1H), 7.58-7.52 (m, 2H), 7.49-7.35 (m, 6H), 6.96 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 3.77-3.62 (m, 7H), 3.42-3.24 (m, 4H), 3.18-3.11 (m, 1H), 1.37-1.31 (m, 6H); ESI MS m/z 442 [M+H]⁺.

Example 16 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

2-Picoline borane (125 mg, 1.17 mmol) was added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (115 mg, 0.234 mmol) and acetone (0.17 mL, 2.3 mmol) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at reflux overnight. Acetone (0.8 mL) and 2-picoline borane (125 mg, 1.17 mmol) were added to the solution, and the resulting solution was stirred at reflux for 48 h. Acetone (1 mL) and 2-picoline borane (125 mg, 1.17 mmol) were added to the solution, and the resulting solution was stirred at reflux for 72 h. The solution was cooled and adjusted to pH 7 with saturated NaHCO₃ solution. The resulting solution was diluted with CH₂Cl₂. The phases were separated, and the organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded an white powder. Preparative TLC (9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) afforded 35 mg of a white powder. 2 N HCl in Et₂O (0.04 mL, 0.08 mmol) was added to a solution of the off-white solid in 1:1 CH₂Cl₂/MeOH (5 mL) under N₂, and the resulting solution was stirred at 25° C. for 10 min. The solution was concentrated under reduced pressure to afford the title compound (35 mg, 30%) as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br s, 1H), 8.62 (d, J=3.0 Hz, 1H), 7.83 (ddd, J=8.5, 8.5, 3.0 Hz, 1H), 7.65 (dd, J=9.0, 5.0 Hz, 1H), 7.57-7.52 (m, 2H), 7.44 (d, J=2.0 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.13 (dd, J=8.0, 3.0 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.22 (s, 2H), 3.78-3.62 (m, 6H), 3.43-3.11 (m, 6H), 1.48-1.39 (m, 6H); ESI MS m/z 461 [M+H]⁺.

Example 17 Preparation of 4-(Benzyloxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

2-Picoline borane (75 mg, 0.70 mmol) was added to a solution of 4-(benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (59 mg, 0.14 mmol) and acetone (1 mL) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at reflux for 24 h. Additional acetone (1 mL) and 2-picoline borane (75 mg, 0.70 mmol) were added to the solution, and the resulting solution was stirred at reflux for 24 h. The solution was cooled, H₂O was added, and the resulting biphasic solution was adjusted to pH 7 with saturated NaHCO₃ solution. The phases were separated, and the organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. 2 N HCl in Et₂O (0.04 mL, 0.08 mmol) was added to a solution of the white solid in 1:1 CH₂Cl₂/MeOH (5 mL) under N₂, and the resulting solution was stirred at 25° C. for 15 min. The solution was concentrated under reduced pressure to afford the title compound (35 mg, 54%) as a white powder: mp 152-155° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.19 (s, 1H), 9.71 (br s, 1H), 7.55-7.36 (m, 7H), 7.26 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.0, 1.5 Hz, 1H), 6.08 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.14 (s, 2H), 3.75-3.61 (m, 3H), 3.36-3.05 (m, 6H), 1.36-1.30 (m, 6H); ESI MS m/z 428 [M+H]⁺.

Example 18 Preparation of 4-(Benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 7-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (CAS Registry Number 847987-95-5) (WO 2005/023245 to Boggs et al., which is hereby incorporated by reference in its entirety)

MeOH (60 mL) and 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.60 g, 10.4 mmol) were added to a solution of periodic acid (4.76 g, 20.8 mmol) in 1:1 MeOH/H₂O (50 mL), cooled to 0° C., and the resulting slurry was warmed to ambient temperature with stirring for 18 h. The mixture was concentrated to dryness. The resulting solids were dissolved in CHCl₃ (100 mL), and the resulting solution was washed with 10% Na₂CO₃ (2×100 mL) and 10% Na₂SO₃ (2×50 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The solids were washed with MeOH (75 mL) and dried to yield the title compound (1.86 g, 68%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.73 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.21 (d, J=8.5, 2.0 Hz, 1H), 2.94 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H), 2.17-2.12 (m, 2H).

b) 7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one

Cs₂CO₃ (2.5 g, 7.5 mmol) and iodomethane (0.47 mL, 7.5 mmol) were added to a solution of 7-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.7 g, 6.3 mmol) in DMF (21 mL), and the resulting mixture was stirred for 4 h at ambient temperature. The reaction was diluted with H₂O (25 mL), and the resulting solution was stirred for 15 minutes. The resulting precipitate was collected by filtration, washed with H₂O (200 mL) and dried to yield the title compound (1.5 g, 87%) as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J=1.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.25 (dd, J=8.5, 1.5 Hz, 1H), 3.98 (s, 3H), 2.96 (t, J=6.0 Hz, 2H), 2.57 (t, J=6.0 Hz, 2H), 2.13-2.10 (m, 2H).

c) 7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one oxime

Hydroxylamine hydrochloride (0.56 g, 8.1 mmol) and sodium acetate (0.66 g, 8.1 mmol) were added to a suspension of 7-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 5.4 mmol) in EtOH (14 mL) and H₂O (5.0 mL), and the resulting suspension was heated at reflux for 18 h. The reaction was cooled and concentrated to dryness. The resulting solid was triturated with MeOH (100 mL), and the solids were dried to yield the title compound (1.4 g, 90%) as an off-white powder: ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (s, 1H), 7.66 (s, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.15 (dd, J=8.5, 1.0 Hz, 1H), 3.95 (s, 3H), 2.79-2.72 (m, 4H), 1.88-1.83 (m, 2H).

d) 8-Bromo-10-methyl-2,3,4,5-tetrahydroazepino[3,4-b]indol-2(10H)-one

A suspension of 7-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one oxime (1.4 g, 4.9 mmol) in PPA (32 g) was mechanically rotated in a water bath set at 100° C. for 5 h. The reaction was placed in an ice bath and slowly quenched with H₂O (80 mL). The solution was made neutral by addition of 6 N NaOH and extracted with CH₂Cl₂ (6×25 mL). The combined organic extracts were concentrated to dryness. Flash purification (40 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 0:100 over 20 column volumes and held for 5 column volumes) followed by flash chromatography (40 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 70:30 over 20 column volumes) provided the title compound (0.21 g, 15%) as a light yellow foam: ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (t, J=5.7 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.4, 1.8 Hz, 1H), 3.85 (s, 3H), 3.15-3.10 (m, 2H), 2.95 (t, J=7.2 Hz, 2H), 1.97-1.94 (m, 2H); ESI MS m/z 293 [M+H]⁺.

e) tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

BH₃.THF (1.0 M solution in THF, 9 mL) was slowly added to a solution of 8-bromo-10-methyl-2,3,4,5-tetrahydroazepino[3,4-b]indol-2(10H)-one (0.19 g, 0.66 mmol) in THF (11 mL) and the resulting solution was heated at reflux for 18 h. The reaction was cooled and 12 N HCl (˜4 mL) was added slowly until gas evolution ceased. The resulting solution was diluted with H₂O (25 mL) and heated at reflux for 3 h. The solution was cooled and made basic (˜pH 9.5) by slow addition of 6 N NaOH. The resulting solution was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated to afford a crude yellow oil. DMAP (10 mg, catalytic) and Boc₂O (0.19 g, 0.85 mmol) were added to a solution of the yellow oil in CH₂Cl₂ (2.5 mL) under N₂, and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with H₂O (10 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO (1:1 hex/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH, 100:0 for 8 column volumes, increased to 50:50 over 12 column volumes and held for 5 column volumes) followed by flash chromatography (12 g ISCO, hexanes/EtOAc, 90:10 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 2 column volumes) provided the title compound (0.15 g, 60%) as a white film: ¹H NMR (500 MHz, DMSO-d₆) δ 7.64 (s, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.60 (s, 2H), 3.70 (s, 3H), 3.64-3.62 (m, 2H), 2.79 (t, J=6.0 Hz, 2H), 1.81-1.80 (m, 2H), 1.36-1.32 (m, 9H).

f) tert-Butyl-8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (0.13 g, 0.34 mmol), 4-benzyloxy pyridinone (69 mg, 0.34 mmol), and Cs₂CO₃ (0.12 g, 0.38 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (16 mg, 0.12 mmol) and copper iodide (78 mg, 0.41 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (80 mL). The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (4×20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 10 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes) gave the title compound (56 mg, 32%) as a yellow film: ¹H NMR (500 MHz, CDCl₃) δ 7.55-7.52 (m, 1H), 7.42-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.10-6.09 (m, 1H), 6.04-6.03 (m, 1H), 5.05 (s, 2H), 4.66-4.63 (m, 2H), 3.75-3.67 (m, 5H), 2.92-2.91 (m, 2H), 1.94-1.89 (m, 2H), 1.43-1.42 (m, 9H).

g) 4-(Benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl-8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (54 mg, 0.11 mmol) in CH₂Cl₂ (2.0 mL), and the resulting solution was stirred at ambient temperature for 30 min. The mixture was carefully quenched with saturated NaHCO₃ solution until the solution was basic. The mixture was extracted with CH₂Cl₂ (3×25 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄ and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 0:100 over 20 column volumes and held for 15 column volumes) provided the title compound (31 mg, 73%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.53 (d, J=8.5 Hz, 1H), 7.43-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.0, 1.5 Hz, 1H), 6.08 (d, J=2.5 Hz, 1H), 6.03 (dd, J=7.5, 3.0 Hz, 1H), 5.05 (s, 2H), 4.10 (s, 2H), 3.64 (s, 3H), 3.23 (t, J=5.5 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 1.90-1.86 (s, 2H); ESI MS m/z 400 [M+H]⁺.

h) 4-(Benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A solution of 4-(benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-one (30 mg, 0.075 mmol) in CH₂Cl₂ (1.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (75 μL, 0.075 mmol), and the resulting solution was stirred at ambient temperature for 1 h. The solution was concentrated to dryness, diluted with H₂O and lyophilized to yield the title compound (32 mg, 99%) as a yellow powder: mp 210-218° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.59-7.55 (m, 2H), 7.48-7.41 (m, 5H), 7.38-7.36 (m, 1H), 6.97 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.53 (s, 2H), 3.74 (s, 3H), 3.49-3.47 (m, 2H), 2.97 (t, J=5.0 Hz, 2H), 1.99-1.97 (m, 2H); ESI MS m/z 400 [M+H]⁺; HPLC (Method A) 97.9% (AUC), t_(R)=14.8 min.

Example 19 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin 2(1H)-one hydrochloride

a) tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (0.13 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (4×20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) provided the title compound (0.12 g, 59%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (d, J=2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.40 (d, J=4.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.11 (d, J=8.0, 3.0 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 4.65-4.63 (m, 2H), 3.72 (s, 3H), 3.67-3.66 (m, 2H), 2.86-2.85 (m, 2H), 1.82-1.81 (m, 2H), 1.36-1.34 (m, 9H); ESI MS m/z 519 [M+H]⁺.

b) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin 2(1H)-one

A solution of tert-butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (0.12 mg, 0.23 mmol) in 4:1 MeOH/CH₂Cl₂ (5.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (46 mL), and the resulting solution was stirred at ambient temperature for 2 h. The solids were collected by filtration, washed with Et₂O and dried. Preparative TLC (Analtech, 20×20 cm, 1000 microns, 80:18:2 CH₂Cl₂/MeOH/NH₄OH) afforded the title compound (41 mg, 43%) as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (d, J=2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.34 (s, 1H), 6.87 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 5.21 (s, 2H), 4.0 (s, 2H), 3.64 (s, 3H), 3.06 (t, J=5.5 Hz, 2H), 2.83 (t, J=5.5 Hz, 2H), 1.77-1.76 (m, 2H); ESI MS m/z 419 [M+H]⁺.

c) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin 2(1H)-one hydrochloride

1.25 M HCl in MeOH (75 μL, 0.094 mmol) was added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin 2(1H)-one (39 mg, 0.094 mmol) in MeOH (2.0 mL), and the resulting solution was stirred at ambient temperature for 1 h. The mixture was concentrated to dryness under reduced pressure to yield the title compound (36 mg, 85%) as a light yellow powder: mp 268-275° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 8.19 (br s, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.58-7.51 (m, 2H), 7.45 (d, J=1.5 Hz, 1H), 6.95 (dd, J=8.0, 3.0 Hz, 1H), 6.12 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.21 (s, 2H), 4.39 (s, 2H), 3.71 (s, 3H), 3.38-3.36 (m, 2H), 2.95-2.93 (m, 2H), 1.93-1.92 (m, 2H); ESI MS m/z 419 [M+H]⁺; HPLC (Method A) 98.3% (AUC), t_(R)=13.0 min.

Example 20 Preparation of 1-(10-Methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)-4-(5-trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 10-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.13 g, 0.54 mmol), and Cs₂CO₃ (0.19 g, 0.60 mmol) were suspended in DMSO (3.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (23 mg, 0.16 mmol) and copper iodide (0.13 g, 0.59 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×25 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 20 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (62 mg, 20%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.35-7.32 (m, 1H), 7.28-7.26 (s, 1H), 7.08-7.02 (m, 2H), 4.68-4.64 (m, 2H), 3.78-3.74 (m, 4H), 3.71-3.69 (m, 1H), 2.95-2.94 (m, 2H), 1.96-1.91 (m, 2H), 1.43 (s, 9H); ESI MS m/z 539 [M+H]⁺.

b) 1-(10-Methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)-4-(5-trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

Anhydrous 1.0 M HCl in diethyl ether (23 mL) was added to a solution of tert-butyl 10-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (60 mg, 0.11 mmol) in 4:1 MeOH/CH₂Cl₂ (5.0 mL), and the resulting solution was stirred at ambient temperature for 2 h. The solids were collected by filtration, washed with Et₂O and dried to yield the title compound (47 mg, 87%) as a yellow powder: mp 288-296° C. decomp; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.12 (br s, 2H), 8.40-8.34 (m, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.10-7.06 (m, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.50-3.49 (m, 2H), 3.01-2.98 (m, 2H), 2.00-1.98 (m, 2H); ESI MS m/z 439 [M+H]⁺; HPLC (Method A) 99.8% (AUC), t_(R)=14.5 min.

Example 21 Preparation of 4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 7-Bromo-2,3,4,9-tetrahydro-1H-carbazole (CAS Registry Number 78863-99-7) (Plant et al., Journal of the Chemical Society, 237-239 (1939), which is hereby incorporated by reference in its entirety)

Cyclohexanone (7.7 mL, 73 mmol) was added to a suspension of 3-bromophenyl hydrazine hydrochloride (15 g, 67 mmol) in EtOH (150 mL) and 12 N HCl (30 mL), and the resulting suspension was heated at reflux for 1 h. The suspension was cooled and diluted with H₂O (200 mL). The resulting solids were collected by filtration. The solids were dissolved in EtOAc, and the solution was made basic with saturated NaHCO₃ solution. The resulting solution was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness. The solids were suspended in CH₂Cl₂ (˜100 mL) and collected by filtration. The solids were washed with MeOH (50 mL) and dried under reduced pressure to provide the title compound (5.74 g, 33%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.35 (d, J=1.5 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 2.70 (t, J=6.0 Hz, 2H), 2.64 (t, J=5.5 Hz, 2H), 1.91-1.84 (m, 4H).

b) 7-Bromo-2,3-dihydro-1H-carbazol-4(9H)-one

A solution 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.87 g, 11.5 mmol) in THF (103 mL) and H₂O (11.5 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.23 g, 23.1 mmol) in THF (46 mL) at such a rate that the reaction mixture did not exceed 4° C. The resulting solution was allowed to stir for an additional 45 min at 0° C. The solution was concentrated to dryness under reduced pressure. The resulting solids were suspended in EtOAc (100 mL) and saturated NaHCO₃ solution (300 mL). The solids were collected by filtration and washed with additional saturated NaHCO₃ solution (400 mL) followed by H₂O (150 mL). The solid was dried to provide the title compound (2.46 g, 81%) as a light pink solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.97 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 2.0 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.14-2.09 (m, 2H); ESI MS m/z 263 [M+H]⁺.

c) 7-Bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one

Sodium hydride (60% dispersion in oil, 0.342 g, 8.55 mmol) was added to a solution of 7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one (2.46 g, 9.35 mmol) in DMF (33 mL) at room temperature under N₂ and stirred for 15 min. Methyl iodide (1.99 mL, 14.0 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H₂O (80 mL), upon which a solid precipitated out of solution. The solids were collected by filtration and were washed thoroughly with water followed by hexanes to provide the title compound (2.43 g, 94%) as a tan solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (d, J=8.5 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.5, 1.5 Hz, 1H), 3.71 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.15-2.10 (m, 2H).

d) 7-Bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime

Hydroxylamine hydrochloride (3.21 g, 46.5 mmol) and sodium acetate (3.81 g, 46.5 mmol) were added to a suspension of 7-bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one (8.61 g, 30.9 mmol) in EtOH (79.0 mL) and H₂O (27.0 mL), and the resulting suspension was heated at reflux for 20 h. The reaction was cooled to ˜40° C., and the solids were collected by filtration. The solids were washed with H₂O and EtOH. The solids were divided into two batches of 3.93 g and 4.08 g and recrystallized in CH₃CN (500 mL per batch). The material was allowed to crystallize for two days the resulting crystals were collected by filtration to afford the title compound (6.31 g, 70%) as an off-white crystalline solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.33 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.0, 1.5 Hz, 1H), 3.66 (s, 3H), 2.81 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H). Additional material was obtained by concentrating the filtrate to 200 mL and collecting the resulting solids to afford the title compound (1.22 g, 13%) as an off-white powder.

e) 8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

Two batches of a suspension of 7-bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime (3.76 g, 12.8 mmol) in PPA (58 g) were mechanically rotated in a water bath set at 100° C. for 4.5 h. The batches were placed in an ice bath and slowly quenched with H₂O. The flasks were sonicated, and the resulting solids were isolated by filtration. The solids were washed with water, 1N NaOH (300 mL), and copious H₂O until ˜pH 7 was reached. The resulting solids were dried to afford the title compound (7.15 g, 95%) as a slightly pink solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=8.4 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.58-7.55 (m, 1H), 7.20 (dd, J=8.4, 1.5 Hz, 1H), 3.67 (s, 3H), 3.20-3.16 (m, 2H), 3.08 (t, J=6.6 Hz, 2H), 2.07-2.00 (m, 2H).

f) tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

BH₃.THF (1.0 M solution in THF, 298 mL) was slowly added to a solution of 8-bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (6.50 g, 22 mmol) in THF (371 mL), and the resulting solution was heated at reflux for 24 h. The reaction was cooled, and 12 N HCl solution (˜40 mL) was added slowly over 1 h. The solution was diluted with H₂O (400 mL) and reheated at reflux for 4.5 h. The solution was cooled and made basic (pH˜9.5) by slow addition of 6 N NaOH. The solution was extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to provide a crude yellow oil. DMAP (300 mg, catalytic) and Boc₂O (6.3 g, 29 mmol) were added to a solution of the yellow oil in CH₂Cl₂ (84 mL) under N₂, and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with H₂O and extracted with CH₂Cl₂ (3×25 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (120 g ISCO hexanes/EtOAc, 95:5 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) provided the title compound (6.21 g, 72%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (d, J=1.5 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4, 1.5 Hz, 1H), 4.52-4.49 (m, 2H), 3.62-3.59 (m, 5H), 2.94-2.90 (m, 2H), 1.87-1.85 (m, 2H), 1.33-1.21 (m, 9H).

g) tert-Butyl 8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.12 g, 0.33 mmol), 4-benzyloxy pyridinone (65 mg, 0.33 mmol), and Cs₂CO₃ (0.12 g, 0.38 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (14 mg, 0.098 mmol) and copper iodide (74 mg, 0.39 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 133° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (25 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL), and the resulting solution was filtered through silica gel. The filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with H₂O (1×25 mL) and brine (3×50 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 10 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes) gave the title compound (88 mg, 54%) as a yellow foam: ¹H NMR (500 MHz, CDCl₃) δ 7.63-7.52 (m, 2H), 7.42-7.36 (m, 5H), 7.31 (d, J=7.5 Hz, 1H), 6.99 (d, J=7.0 Hz, 1H), 6.10-6.09 (m, 1H), 6.04-6.03 (m, 1H), 5.05 (s, 2H), 4.71-4.62 (m, 2H), 4.14-4.10 (m, 5H), 2.97-2.96 (m, 2H), 2.04-2.03 (m, 2H), 1.44-1.37 (m, 9H).

h) 4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (88 mg, 0.18 mmol) in CH₂Cl₂ (1.0 mL) and the resulting solution was stirred at ambient temperature for 1 h. The mixture was carefully made basic with saturated NaHCO₃ solution. The mixture was extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts were washed with brine (125 mL), dried over Na₂SO₄, and concentrated under reduced pressure to dryness. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 0:100 over 20 column volumes and held for 5 column volumes) provided the title compound (46 mg, 69%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.49 (d, J=8.5 Hz, 1H), 7.43-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.23 (d, J=1.5 Hz, 1H), 6.79 (dd, J=8.5, 2.0 Hz, 1H), 6.08 (d, J=3.0 Hz, 1H), 6.03 (dd, J=8.0, 3.0 Hz, 1H), 5.05 (s, 2H), 4.08 (s, 2H), 3.66 (s, 3H), 3.25 (t, J=5.5 Hz, 2H), 2.98 (t, J=5.5 Hz, 2H), 1.94-1.89 (m, 2H); ESI MS m/z 400 [M+H]⁺.

i) 4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A solution of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one (45 mg, 0.11 mmol) in CH₂Cl₂ (2.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (0.11 mL, 0.11 mmol), and the resulting solution was stirred at ambient temperature for 1 h. The solution was concentrated to dryness, diluted with H₂O and lyophilized to yield the title compound (47 mg, 95%) as an off-white powder: mp 283-287° C., decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.38-7.36 (m, 1H), 6.99 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.44-4.43 (m, 2H), 3.71 (s, 3H), 3.45-3.43 (m, 2H), 3.09 (t, J=6.0 Hz, 2H), 2.06-2.04 (m, 2H); ESI MS m/z 400 [M+H]⁺; HPLC (Method A) 98.2% (AUC), t_(R)=14.3 min.

Example 22 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(5-(fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.11 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL) and filtered through silica gel. The filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×25 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (0.12 g, 57%) as an off-white film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (d, J=3.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.11 (d, J=7.5 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.21 (s, 2H), 4.58 (s, 2H), 3.66-3.64 (m, 5H), 2.99-2.97 (m, 2H), 1.93-1.89 (m, 2H), 1.35-1.28 (m, 9H).

b) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl))pyridin-2(1H)-one hydrochloride

A solution of 4-(2-fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (53 mg, 0.093 mmol) in 1.25 M HCl in MeOH (6.0 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness under reduced pressure to provide the title compound (49 mg, quantitative) as a brown-yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 2H), 8.62 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.85-7.81 (m, 1H), 7.67-7.63 (m, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 6.99 (dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.22 (s, 2H), 4.43-4.41 (m, 2H), 3.71 (s, 3H), 3.43-3.39 (m, 2H), 3.09 (t, J=5.0 Hz, 2H), 2.07-2.05 (m, 2H); ESI MS m/z 419 [M+H]⁺; HPLC (Method A) 96.5% (AUC), t_(R)=12.5 min.

Example 23 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.13 g, 0.54 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×25 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (84 mg, 40%) as a yellow film: ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.33 (s, 1H), 7.26 (s, 1H), 7.07-7.02 (m, 2H), 4.73-4.64 (m, 2H), 3.76-3.67 (m, 5H), 2.99-2.98 (m, 2H), 2.05-2.04 (m, 2H), 1.44-1.38 (m, 9H); ESI MS m/z 539 [M+H]⁺.

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

A solution of tert-butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (80 mg, 0.20 mmol) in 5:1 MeOH/CH₂Cl₂ (6.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (32 mL), and the resulting suspension was stirred at ambient temperature for 1 h. The solids were collected by filtration, washed with Et₂O and dried to yield the title compound (58 mg, 85%) as a yellow powder: mp 264-270° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.89 (s, 2H), 8.39 (dd, J=8.5, 2.0 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.0, 1.5 Hz, 1H), 7.07 (d, J=7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.47-3.45 (m, 2H), 3.11 (t, J=5.0 Hz, 2H), 2.08-2.06 (m, 2H); ESI MS m/z 439 [M+H]⁺; HPLC (Method A) 95.1% (AUC), t_(R)=14.7 min.

Example 24 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4((6-trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (0.14 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel, and the filtrate concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (4×20 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (61 mg, 27%) as an off-white foam: ¹H NMR (500 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.19 (dd, J=8.0, 1.5 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.13 (dd, J=7.5, 2.5 Hz, 1H), 6.01 (d, J=3.0 Hz, 1H), 5.34 (s, 2H), 4.58 (s, 2H), 3.66-3.64 (m, 5H), 2.98-2.97 (m, 2H), 1.93-1.89 (m, 2H), 1.35-1.28 (m, 9H).

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride

A solution of tert-butyl 6-methyl-8-(2-oxo-4((6-trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (53 mg, 0.093 mmol) in 1.25 M HCl in MeOH (6.0 mL) was stirred at ambient temperature for 18 h. The solution was concentrated to dryness, diluted with H₂O and lyophilized to yield the title compound (49 mg, quant.) as a brown-yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s, 2H), 8.89 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 6.99 (dd, J=8.5, 1.5 Hz, 1H), 6.15 (dd. J=7.5, 2.5 Hz, 1H), 6.01 (d, J=2.5 Hz, 1H), 5.35 (s, 2H), 4.42 (s, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H), 3.10-3.09 (m, 2H), 2.07-2.06 (m, 2H); ESI MS m/z 469 [M+H]⁺; HPLC (Method A) 98.8% (AUC), t_(R)=14.2 min.

Example 25 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimdin-5-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (0.12 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×20 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (40 mg, 19%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 9.50 (s, 2H), 7.90-7.88 (m, 1H), 7.54-7.50 (m, 2H), 7.12 (d, J=1.5 Hz, 1H), 7.04-7.02 (m, 1H), 6.85 (dd, J=7.0, 2.0 Hz, 1H), 4.60 (s, 2H), 3.69-3.65 (m, 5H), 3.01-3.00 (m, 2H), 1.94-1.91 (m, 2H), 1.36-1.30 (m, 9H).

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimdin-5-yl)pyridin-2(1H)-one hydrochloride

A solution of tert-butyl 6-methyl-8-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (38 mg, 0.071 mmol) in 1.25 M HCl in MeOH (10.0 mL) was stirred at ambient temperature for 18 h. The solution was concentrated to dryness, diluted with H₂O and lyophilized to provide the title compound (28 mg, 83%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 8.93 (s, 2H), 7.89 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.12-7.09 (m, 2H), 6.87 (dd, J=7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.46-3.40 (m, 2H), 3.12-3.11 (m, 2H), 2.08-2.07 (m, 2H); ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 98.2% (AUC), t_(R)=14.1 min.

Example 26 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridine-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (0.13 g, 0.54 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×20 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (81 mg, 38%) as a yellow film: ¹H NMR (500 MHz, CDCl₃) δ 7.74 (s, 4H), 7.68-7.51 (m, 2H), 7.33 (s, 1H), 7.07-7.04 (m, 1H), 6.92-6.91 (m, 1H), 6.49 (d, J=6.0 Hz, 1H), 4.72-4.64 (m, 2H), 3.76-3.67 (m, 5H), 2.98 (t, J=6.0 Hz, 2H), 2.06-2.02 (m, 2H), 1.44-1.38 (m, 9H); ESI MS m/z 538 [M+H]⁺.

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochloride

A solution of tert-butyl 6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridine-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (75 mg, 0.13 mmol) in 4:1 MeOH/CH₂Cl₂ (5.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (28 mL), and the reaction mixture was stirred at ambient temperature for 2 h. The solids were collected by filtration, washed with Et₂O and dried to yield the title compound (57 mg, 86%) as a yellow powder: mp 264-270° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (s, 2H), 8.01 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.80 (d, J=7.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.5, 2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.72 (dd, J=7.5, 2.5 Hz, 1H), 4.55-4.46 (m, 2H), 3.73 (s, 3H), 3.46-3.45 (m, 2H), 3.11 (t, J=5.5 Hz, 2H), 2.08-2.06 (m, 2H); ESI MS m/z 438 [M+H]⁺; HPLC (Method A) 97.1% (AUC), t_(R)=15.7 min.

Example 27 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.11 g, 0.29 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (83 g, 0.35 mmol) and Cs₂CO₃ (0.10 g, 0.32 mmol) were suspended in DMSO (1.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (13 mg, 0.087 mmol) and copper iodide (72 mg, 0.38 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×20 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (67 mg, 42%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.50-8.48 (m, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.54-7.51 (m, 2H), 7.03-6.99 (m, 2H), 6.78 (dd, J=7.5, 2.0 Hz, 1H), 4.60 (s, 2H), 3.69-3.65 (m, 5H), 3.00-2.99 (m, 2H), 1.96-1.90 (m, 2H), 1.36-1.30 (m, 9H); ESI MS m/z 539 [M+H]⁺.

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride

A solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (67 mg, 0.13 mmol) in 1.25 M HCl in MeOH (16 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness under reduced pressure and diluted with MeOH (2.0 mL) and Et₂O (25 mL). The resulting solids were collected by filtration and dried to yield the title compound (42 mg, 70%) as a yellow powder: mp 274-280° C. decomp; ¹H NMR (500 MHz, DMSO-d₆) δ 9.50 (s, 2H), 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.09 (dd, J=8.5, 2.0 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.80 (d, J=7.5, 2.0 Hz, 1H), 4.42-4.41 (m, 2H), 3.73 (s, 3H), 3.43-3.41 (m, 2H), 3.11 (t, J=6.0 Hz, 2H), 2.10-2.08 (m, 2H); ESI MS m/z 439 [M+H]⁺; HPLC (Method A) 99.0% (AUC), t_(R)=13.7 min.

Example 28 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.21 g, 0.56 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.16 g, 0.68 mmol) and Cs₂CO₃ (0.20 g, 0.61 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol) and copper iodide (0.14 g, 0.72 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×20 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (110 mg, 37%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (d, J=9.0 Hz, 1H), 8.45 (d, J=9.0 Hz, 1H), 7.91 (d, J=7.0 Hz, 1H), 7.55-7.54 (m, 2H), 7.37 (d, J=1.5 Hz, 1H), 7.16 (dd, J=7.0, 1.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 3.70-3.66 (m, 5H), 3.01-3.00 (m, 2H), 1.95-1.91 (m, 2H), 1.36-1.30 (m, 9H); ESI MS m/z 540 [M+H]⁺.

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

A solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.11 g, 0.20 mmol) in 1.25 M HCl in MeOH (25 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness and diluted with MeOH (5.0 mL) and Et₂O (25 mL). The resulting solids were collected by filtration and dried to provide the title compound (77 mg, 80%) as a yellow solid: mp 248-252° C. decomp; ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 2H), 8.71 (d, J=9.0 Hz, 1H), 8.46 (d, J=8.5 Hz, 1H), 7.91 (d, J=7.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.17 (dd, J=7.0, 2.0 Hz, 1H), 7.13 (dd, J=8.5, 1.5 Hz, 1H), 4.46-4.45 (m, 2H), 3.75 (s, 3H), 3.46-3.44 (m, 2H), 3.12 (t, J=5.5 Hz, 2H), 2.08-2.07 (m, 2H); ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 99.2% (AUC), t_(R)=13.2 min.

Example 29 Preparation of 4-(Benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 4-(Benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (54 mg, 0.12 mmol) and 37% aqueous formaldehyde (15 μL, 0.17 mmol) were dissolved in 1:1 MeOH/CH₂Cl₂ (1.0 mL), and the resulting solution was stirred at room temperature for 5 min. Sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added, and the reaction stirred at room temperature for an additional 45 min. The mixture was neutralized with saturated NaHCO₃ solution and extracted with CH₂Cl₂ (2×10 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) provided the title compound (24 mg, 46%) as a yellow film: ¹H NMR (300 MHz, CD₃OD) δ 7.60-7.55 (m, 2H), 7.47-7.35 (m, 6H), 7.01-6.98 (m, 1H), 6.29-6.26 (m, 1H), 6.11 (d, J=2.7 Hz, 1H), 5.48 (s, 2H), 5.17 (s, 2H), 4.16-4.10 (m, 2H), 3.74-3.73 (m, 3H), 3.10-3.06 (m, 2H), 2.61 (s, 3H), 2.12-2.06 (m, 2H).

b) 4-(Benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

1.25 M HCl in MeOH (88 μL) was added to a solution of 4-(benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one (23 mg, 0.056 mmol) in MeOH (1.0 mL), and the resulting solution was stirred at ambient temperature for 1.5 h under N₂. The mixture was partially concentrated under reduced pressure, diluted with water, and lyophilized to yield the title compound (23 mg, 98%) as a yellow powder; ¹H NMR (500 MHz, DMSO-d₆) δ 10.02 (br s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.49-7.36 (m, 6H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.73-4.71 (m, 1H), 4.52-4.47 (m, 1H), 3.72 (s, 3H), 3.68-3.63 (m, 1H), 3.44-3.41 (m, 1H), 3.16-3.03 (m, 2H), 2.81-2.80 (m, 3H), 2.17-2.01 (m, 2H); ESI MS m/z 414 [M+H]⁺; HPLC (Method A) 98.3% (AUC), t_(R)=14.3 min.

Example 30 Preparation of 4-(Benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 4-(Benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

Acetaldehyde (50 μL, 0.88 mmol) and picoline borane complex (47 mg, 0.43 mmol) were added to a suspension of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (64 mg, 0.18 mmol) in 10:1 CH₂Cl₂/AcOH (5.0 mL), and the resulting solution was stirred at ambient temperature for 2 h. Additional acetaldehyde (50 μL, 0.88 mmol) was added to the solution, and the resulting mixture was stirred for 18 h. The mixture was neutralized with saturated NaHCO₃ solution and extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) provided the title compound (34 mg, 54%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.56 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.39-7.37 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.14 (s, 2H), 3.88 (s, 2H), 3.66 (s, 3H), 3.03-3.01 (m, 2H), 2.94 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 2H), 1.78-1.76 (m, 2H), 1.01 (t, J=7.0 Hz, 3H); ESI MS m/z 428 [M+H]⁺.

b) 4-(Benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

Following the procedure for Example 29 (step b), but substituting 4-(benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one (33 mg, 0.080 mmol) for 4-(benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one, the title compound (33 mg, 91%) was prepared as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.34 (br s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.47-7.41 (m, 5H), 7.39-7.35 (m, 1H), 6.99 (dd, J=8.0, 1.0 Hz, 1H), 6.09 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.51 (s, 2H), 3.71 (s, 3H), 3.47-3.44 (m, 2H), 3.09-3.08 (m, 2H), 2.97-2.95 (m, 2H), 2.08-2.05 (m, 2H), 1.22 (t, J=6.5 Hz, 3H); ESI MS m/z 428 [M+H]⁺; HPLC (Method A) 98.8% (AUC), t_(R)=15.2 min.

Example 31 Preparation of 4-(Benzyloxy)-1-(2-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 4-(Benzyloxy)-1-(2-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

Acetone (2.81 mL) and picoline borane complex (59 mg, 0.55 mmol) were added to a suspension of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (80 mg, 0.18 mmol) in 10:1 CH₂Cl₂/AcOH (3.1 mL) and the resulting solution was stirred at reflux for 18 h. Acetone (1.0 mL) and picoline borane complex (50 mg, 0.46 mmol) were added to the solution and the resulting mixture was stirred for 48 h. The mixture was partitioned with H₂O (5 mL) and CH₂Cl₂ (20 mL) and extracted with CH₂Cl₂ (2×20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) followed by preparative TLC (Analtech, 20×20 cm, 1000 microns, 50:50 (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH) provided a white solid that upon concentration with 1.25 M HCl in MeOH (2.0 mL) afforded the title compound (33 mg, 38%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.92 (br s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.50-7.35 (m, 6H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.65-4.53 (m, 2H), 3.72 (s, 3H), 3.57-3.47 (m, 3H), 3.11 (t, J=6.0 Hz, 2H), 2.24-2.07 (m, 2H), 1.34-1.30 (m, 6H); ESI MS m/z 442 [M+H]⁺; HPLC (Method A, 223 nm) 98.4% (AUC), t_(R)=15.7 min.

Example 32 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-(methylthio)phenyl)pyridin-2(1H)-one hydrochloride

a) 4-(4-(Methylthio)phenyl)pyridin-2(1H)-one (CAS Registry Number 1173157-45-3) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety)

A suspension of 4-bromo-2-methoxypyridine (1.225 g, 6.511 mmol), 4-methylthiophenyl boronic acid (2.188 g, 13.02 mmol), PdCl₂(dppf) (531 mg, 0.651 mmol), and K₂CO₃ (1.797 g, 13.02 mmol) in DMSO (10 mL) was degassed under reduced pressure for 25 min. The suspension was put under N₂ and stirred at 95° C. for 16 h. The suspension was cooled, H₂O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded 1.10 g of a white powder. The white powder was diluted with concentrated HCl solution (50 mL) and stirred at reflux for 24 h. The reaction was cooled and concentrated under reduced pressure. The residue was neutralized with saturated NaHCO₃ solution, and the solid was collected by filtration. The solid was washed with H₂O to afford the title compound (1.103 g, 71%) as a tan solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (d, J=8.4 Hz, 2H), 7.43 (d, J=6.9 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 6.57 (d, J=1.7 Hz, 1H), 6.50 (dd, J=6.9, 1.7 Hz, 1H), 3.34 (s, 3H).

b) tert-Butyl 6-methyl-8-(4-4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(4-(methylthio)phenyl)pyridin-2(1H)-one (0.11 g, 0.52 mmol) and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (20 mL), and the resulting solution was washed with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (2×20 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) followed by trituration with MeOH and hot Et₂O provided the title compound (54 mg, 26%) as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 7.75-7.71 (m, 3H), 7.52-7.48 (m, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.66 (d, J=7.0 Hz, 1H), 4.60 (s, 2H), 3.68-3.65 (m, 5H), 3.01-2.99 (m, 3H), 2.53 (s, 3H), 1.94-1.90 (m, 2H), 1.36-1.29 (m, 9H).

c) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-(methylthio)phenyl)pyridin-2(1H)-one hydrochloride

tert-Butyl 6-methyl-8-(4-4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (54 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (6.0 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was partially concentrated under reduced pressure and diluted with Et₂O. The resulting solids were collected by filtration and washed with CH₂Cl₂ to provide the title compound (26 mg, 60%) as a brown powder: mp 250-255° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (br s, 2H), 7.75-7.67 (m, 4H), 7.58 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.5 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J=7.0 Hz, 1H), 4.45 (s, 2H), 3.74 (s, 3H), 3.46-3.45 (m, 2H), 3.12-3.10 (m, 2H), 2.54 (s, 3H), 2.07-2.05 (m, 2H); ESI MS m/z 416 [M+H]⁺; HPLC (Method A) 97.1% (AUC), t_(R)=14.5 min.

Example 33 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.17 g, 0.44 mmol), 4-(6-(methyl)pyridin-3-yl)pyridin-2(1H)-one (90 mg, 0.48 mmol) and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.5 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (19 mg, 0.13 mmol) and copper iodide (0.12 g, 0.66 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (20 mL), and the resulting solution was washed with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (2×20 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (53 mg, 25%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.10-8.08 (m, 1H), 7.76 (d, J=6.5 Hz, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.03-7.01 (m, 1H), 6.84 (s, 1H), 6.71 (d, J=7.0 Hz, 1H), 4.60 (s, 2H), 3.77-3.66 (m, 5H), 3.01-2.99 (m, 2H), 2.54 (s, 3H), 1.99-1.86 (m, 2H), 1.36-1.30 (m, 9H).

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 6-methyl-8-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (50 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (6.0 mL), and the resulting solution was stirred at ambient temperature for 36 h. The solution was partially concentrated under reduced pressure and diluted with Et₂O. The resulting solids were collected by filtration and washed with 99:1 CH₂Cl₂/MeOH to provide the title compound (37 mg, 85%) as a tan solid: mp 245-250° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 9.04 (s, 1H), 8.44 (s, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.58 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J=7.0 Hz, 1H), 4.45. (s, 2H), 3.74 (s, 3H), 3.45-3.44 (m, 2H), 3.11-3.09 (m, 2H), 2.66 (s, 3H), 2.08-2.07 (m, 2H); ESI MS m/z 385 [M+H]⁺; HPLC (Method A) 97.9% (AUC), t_(R)=8.9 min.

Example 34 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride

a) 2-Chloro-4-((6-methylpyridin-3-yl)methoxy)pyridine

(6-Methylpyridin-3-yl)methanol (3.25 g, 26.4 mmol), 2-chloro-4-iodopyridine (5.7 g, 24 mmol), cesium carbonate (10.1 g, 31.2 mmol), CuI (0.90 g, 4.8 mmol) and 1,10-phenanthroline (0.86 g, 4.8 mmol) were stirred in toluene (15 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 100% ethyl acetate) to provide the title compound (4.2 g, 75%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.54 (d, J=2.0 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.65-7.62 (dd, J=7.9, 2.2 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.83-6.80 (dd, J=5.8, 2.2 Hz, 1H), 5.08 (s, 2H), 2.59 (s, 3H).

b) 4-((6-Methylpyridin-3-yl)methoxy)pyridin-2(1H)-one

2-Chloro-4-((6-methylpyridin-3-yl)methoxy)pyridine (4.20 g, 17.9 mmol) and ammonium acetate (6.91 g, 89.7 mmol) were heated at 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO₃ solution. The solid was filtered off to provide the title compound (3.0 g, 77%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.27-11.04 (br s, 1H), 8.51 (s, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.29-7.24 (m, 2H), 5.89 (d, J=7.2 Hz, 1H), 5.82 (s, 1H), 5.05 (s, 2H), 2.50 (s, 3H).

c) tert-Butyl 6-methyl-8-(4-((6-methyl pyridine-3-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one (90 mg, 0.46 mmol) and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (0.11 g, 0.60 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (20 mL) and washed with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (2×20 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 20 column volumes) gave the title compound (0.12 g, 57%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.0, 2.5 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.93-6.91 (m, 1H), 6.07-6.06 (m, 1H), 5.99 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (s, 2H), 3.66-3.64 (m, 5H), 2.99-2.97 (m, 2H), 2.50 (s, 3H), 1.93-1.89 (m, 2H), 1.35-1.28 (m, 9H).

d) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride

tert-Butyl 6-methyl-8-(4-((6-methyl pyridine-3-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.12 g, 0.22 mmol) was treated with 1.25 M HCl in MeOH (13 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was concentrated to dryness to provide the title compound (0.10 g, quantitative) as a brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 2H), 8.89 (s, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 6.98 (dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=8.0, 2.5 Hz, 1H), 6.03 (d, J=2.0 Hz, 1H), 5.33 (s, 2H), 4.44-4.41 (m, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H), 3.10-3.08 (m, 2H), 2.76 (s, 3H), 2.08-2.04 (m, 2H); ESI MS m/z 415 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=9.4 min.

Example 35 Preparation of 4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 7-Bromo-2,3-dihydro-1H-carbazol-4(9H)-one oxime

Hydroxylamine hydrochloride (0.85 g, 12 mmol) and sodium acetate (1.0 g, 12 mmol) were added to a suspension of 7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one oxime (3.0 g, 8.2 mmol) in EtOH (22 mL) and H₂O (7.3 mL), and the resulting suspension was heated at reflux for 6 h. The suspension was cooled and stirred at ambient temperature for 48 h. Additional hydroxylamine hydrochloride (0.43 g, 6.1 mmol) and sodium acetate (0.50 g, 6.1 mmol) were added to the suspension, and the resulting suspension was heated at reflux for 6 h. Hydroxylamine hydrochloride (0.43 g, 6.1 mmol) and sodium acetate (0.57 g, 6.9 mmol) were added to the suspension for a third time, and the suspension was heated at reflux for 18 h. The reaction was cooled and the suspension was concentrated under reduced pressure. The resulting solids were triturated in hot CH₂Cl₂ (100 mL) to provide the title compound (3.44 g, quant.) as a light yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.42 (s, 1H), 10.31 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 7.16 (dd, J=8.5, 1.5 Hz, 1H), 2.78 (t, J=6.5 Hz, 2H), 2.66 (t, J=6.5 Hz, 2H), 1.93-1.88 (m, 2H).

b) 8-Bromo-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

A suspension of 7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one oxime (1.9 g, 5.1 mmol) in PPA (36 g) was mechanically rotated in a water bath set at 100° C. for 4.5 h. The mixture was placed in an ice bath and slowly quenched with H₂O (100 mL). The resulting solids were isolated by filtration. The solids were washed with water, 1N NaOH (50 mL) and H₂O (100 mL) and dried to afford the title compound (1.2 g, 60%) as a light pink powder: ¹H NMR (500 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.12 (d, J=8.5 Hz, 1H), 7.47-7.45 (m, 2H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 3.22-3.19 (m, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.01-1.97 (m, 2H).

c) tert-Butyl 8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

BH₃.THF (1.0 M solution in THF, 53 mL) was slowly added to a solution of 8-bromo-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1.1 g, 3.9 mmol) in THF (66 mL), and the resulting solution was heated at reflux for 48 h. The reaction was cooled to 50° C., additional BH₃.THF (1.0 M solution in THF, 10 mL) was added, and the resulting solution was heated at reflux for 48 h. The reaction was cooled to 50° C., BH₃.THF (1.0 M solution in THF, 10 mL) was added, and the resulting solution was heated to reflux for 18 h. The reaction was cooled to 50° C., BH₃.THF (1.0 M solution in THF, 10 mL) was added for the fourth time, and the resulting solution was heated to reflux for 18 h. The reaction was cooled, and AcOH was added slowly until gas evolution ceased. The resulting solution was concentrated under reduced pressure, and the resulting solids were dissolved in toluene (60 mL) and 12 N HCl (9 mL) and heated at reflux for 2 h. The solution was cooled, partitioned with H₂O (200 mL) and the resulting layers separated. The aqueous phase was made basic with 6 N NaOH, and the resulting solids were collected by filtration. The solids were diluted with 1.2:1 H₂O/i-PrOH (14 mL) under N₂. K₂CO₃ (0.61 g, 4.4 mmol) and Boc₂O (0.97 g, 4.4 mmol) were added to the solution, and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with H₂O (10 mL), and the resulting solids were collected by filtration. Flash chromatography (80 g ISCO hexanes/EtOAc, 90:10 held to 2 column volumes, increase to 50:50 over 12 column volumes and held for 5 column volumes) provided the title compound (0.76 g, 54%) as an off-white film: ¹H NMR (500 MHz, DMSO-d₆) δ 11.03-11.02 (d, J=10.5 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.08 (dd, J=8.5, 1.5 Hz, 1H), 4.51-4.49 (d, J=11.0 Hz, 2H), 3.62 (t, J=5.5 Hz, 2H), 2.90 (t, J=5.5 Hz, 2H), 1.83-1.78 (m, 2H), 1.35-1.23 (m, 9H).

d) tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

6 N NaOH (10 mL), TsCl (0.48 g, 2.5 mmol) and (Bu₄NH)₂SO₄ (50% solution in water, 0.17 mL) were added to a solution of tert-butyl 8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.76 g, 2.1 mmol) in toluene (17 mL), and the resulting solution was stirred for 18 h. Additional TsCl (55 mg, 0.29 mmol) was added, and the reaction was stirred for 18 h. The solution was partitioned with H₂O and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na₂SO₄ and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO hexanes/EtOAC, 90:10 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes) provided the title compound (0.54 g, 50%) as a white foam: ¹H NMR (500 MHz, DMSO-d₆) δ 8.24-8.20 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H) 4.44-4.40 (m, 2H), 3.56 (t, J=5.5 Hz, 2H), 3.20-3.18 (m, 2H), 2.31 (s, 3H), 1.86-1.84 (m, 2H), 1.29-1.03 (m, 9H).

e) tert-Butyl 8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.20 g, 0.39 mmol), 4-benzyloxy pyridinone (0.10 g, 0.51 mmol) and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (96 mg, 0.51 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The solution was further diluted with CH₂Cl₂ (50 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (2×25 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increase to 0:100 over 10 column volumes) gave the title compound (0.14 g, 57%) as a yellow film: ¹H NMR (300 MHz CDCl₃) δ 8.26-8.21 (m, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.44-7.20 (m, 10H), 6.10-6.08 (m, 2H), 5.07 (s, 2H), 4.55-4.46 (m, 2H), 3.67-3.60 (m, 2H), 3.29-3.26 (m, 2H), 2.33 (s, 3H), 1.95-1.94 (m, 2H), 1.40-1.23 (m, 9H).

f) tert-Butyl 8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

NaOH (0.44 g, 11 mmol) was added to a solution of tert-butyl 8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.14 g, 0.22 mmol) in 1:1 CH₂Cl₂/MeOH (20 mL), and the resulting solution was heated at reflux for 18 h. The mixture was diluted with H₂O and was extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to dryness. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 25:75 over 20 column volumes and held for 2 column volumes) provided the title compound (58 mg, 55%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 11.08-11.05 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.48-7.35 (m, 6H), 7.19 (s, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.06 (dd, J=7.0, 2.0 Hz, 1H), 5.95 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 4.55 (s, 2H), 3.65 (t, J=5.0 Hz, 2H), 2.94 (t, J=5.5 Hz, 2H), 1.83-1.80 (m, 2H), 1.35-1.28 (m, 9H).

h) 4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (55 mg, 0.11 mmol) was treated with 1.25 M HCl in MeOH (11 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was concentrated to dryness under reduced pressure. Preparative TLC (Analtech, 20×20 cm, 1000 microns, 80:18:2 CH₂Cl₂/MeOH/NH₄OH) provided an off-white solid, and the resulting solid was treated with 1.25 M HCl in MeOH (1.0 mL). The resulting solution was concentrated to provide the title compound (22 mg, 50%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.45 (s, 1H), 8.90 (s, 2H), 7.61 (d, J=8.5 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.28 (d, J=2.0 Hz, 1H), 6.95 (dd, J=8.0, 2.0 Hz, 1H), 6.08 (dd, J=7.5, 3.0 Hz, 1H), 5.95 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 4.42-4.41 (m, 2H), 3.47-3.45 (s, 2H), 3.03 (t, J=5.0 Hz, 2H), 2.01-1.99 (m, 2H); ESI MS m/z 386 [M+H]⁺; HPLC (Method A) 97.5% (AUC), t_(R)=14.3 min.

Example 36 Preparation of 1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.20 g, 0.39 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.10 g, 0.43 mmol) and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (985 mg, 0.50 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The solution was cooled, diluted with 5:1 MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (50 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×25 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) gave the title compound (98 mg, 37%) as a yellow film: ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.40-8.38 (m, 2H), 8.23-8.18 (m, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.75-7.65 (m, 3H), 7.39-7.33 (m, 4H), 7.12 (dd, J=7.2, 1.8 Hz, 1H), 4.48 (s, 2H), 3.61-3.60 (m, 2H), 3.33-3.27 (m, 2H), 2.31 (s, 3H), 1.89-1.88 (m, 2H), 1.30-1.08 (m, 9H).

b) tert-Butyl 8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

NaOH (0.28 g, 7.1 mmol) was added to a solution of tert-butyl 8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (96 mg, 0.14 mmol) in 1:1 CH₂Cl₂/MeOH (22 mL), and the resulting solution was heated at reflux for 18 h. The mixture was diluted with H₂O and extracted with CH₂Cl₂ (3×20 mL). The organic extracts were concentrated and partitioned with H₂O and EtOAc. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 25:75 over 20 column volumes and held for 8 column volumes) followed by flash chromatography (12 g, ISCO column, Et₂O/(9:1 MeOH/NH₄OH), 100:0 increase to 50:50 over 120 column volumes, increased to 0:100 over 90 column volumes) provided the title compound (32 mg, 43%) as a yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 11.15-11.12 (m, 1H), 9.14 (s, 1H), 8.39-8.32 (m, 2H), 7.82 (d, J=6.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.04 (dd, J=7.0, 1.5 Hz, 1H), 7.00-6.98 (m, 1H), 4.57 (s, 2H), 3.66 (t, J=5.5 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 1.85-1.81 (m, 2H), 1.36-1.29 (m, 9H).

c) 1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (30 mg, 0.057 mmol) was treated with 1.25 M HCl in MeOH (5.5 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was partially concentrated and diluted with Et₂O. The resulting solids were collected by filtration, washed with Et₂O and dried to yield the title compound (13 mg, 51%) as a yellow powder: mp 310-320° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.51 (s, 1H), 9.14 (s, 1H), 8.81 (s, 2H), 8.39 (dd, J=8.5, 2.0 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.08-7.04 (m, 2H), 4.44 (s, 2H), 3.49-3.47 (m, 2H), 3.06-3.04 (m, 2H), 2.03-2.01 (m, 2H); ESI MS m/z 425 [M+H]⁺; HPLC (Method A) 96.9% (AUC), t_(R)=13.7 min.

Example 37 Preparation of 1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.20 g, 0.39 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.10 g, 0.43 mmol), and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (95 mg, 0.50 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL), the resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×25 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 12 column volumes) gave tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (40 mg, 19%) and the title compound (59 mg, 22%) as a yellow film.

Data for tert-Butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate: ¹H NMR (500 MHz, DMSO-d₆) δ 11.17-11.14 (m 1H), 8.69 (d, J=8.5 Hz, 1H), 8.45 (d, J=9.0 Hz, 1H), 7.90 (d, J=7.0 Hz, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.35 (s, 1H), 7.14 (dd, J=7.5, 2.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 4.58 (s, 2H), 3.66 (t, J=5.5 Hz, 2H), 2.96 (t, J=5.5 Hz, 2H), 1.86-1.82 (m, 2H), 1.36-1.30 (m, 9H).

Data for title compound: ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (d, J=9.0 Hz, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.25-8.20 (m, 1H), 8.00 (d, J=6.5 Hz, 1H), 7.75-7.66 (m, 3H), 7.42-7.34 (m, 4H), 7.21 (d, J=8.5 Hz, 1H), 4.49-4.48 (m, 2H), 3.60 (t, J=5.5 Hz, 2H), 2.27 (t, J=5.0 Hz, 2H), 2.31 (s, 3H), 1.90-1.88 (m, 2H), 1.30-1.09 (m, 9H); ESI MS m/z 680 [M+H]⁺.

h) tert-Butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

NaOH (0.17 g, 4.3 mmol) was added to a solution of tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (59 mg, 0.084 mmol) and tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (40 mg, 0.076 mmol) in 1:1 CH₂Cl₂/MeOH (13 mL) and the resulting solution was heated at reflux for 24 h. The mixture was diluted with H₂O (10 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 25:75 over 20 column volumes and held for 8 column volumes) provided the title compound (55 mg, 63%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 11.17-11.14 (m, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.45 (d, J=9.0 Hz, 1H), 7.90 (d, J=7.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.34 (s, 1H), 7.14 (dd, J=7.0, 2.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.58 (s, 2H), 3.66 (t, J=5.0 Hz, 2H), 2.96 (t, J=5.5 Hz, 2H), 1.85-1.82 (m, 2H), 1.36-1.30 (m, 9H).

b) 1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (54 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (9.9 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with Et₂O. The resulting solids were collected by filtration, washed with Et₂O and dried to yield the title compound (33 mg, 70%) as a yellow powder: mp 310-315° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (s, 1H), 8.90 (s, 2H), 8.70 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.16 (dd, J=7.0, 2.0 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 4.44 (s, 2H), 3.48-3.46 (m, 2H), 3.05 (t, J=5.5 Hz, 2H), 2.03-2.01 (m, 2H); ESI MS m/z 426 [M+H]⁺; HPLC (Method A) 97.3% (AUC), t_(R)=12.3 min.

Example 38 Preparation of 4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

a) 8-(4-Benzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (0.20 g, 0.68 mmol), 4-benzyloxy pyridinone (0.18 g, 0.89 mmol), and Cs₂CO₃ (0.24 g, 0.75 mmol) were suspended in DMSO (4.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar and the process repeated. 8-Hydroxyquinoline (30 mg, 0.21 mmol) and copper iodide (0.17 g, 0.89 mmol) were added to the suspension, and the evacuation/Ar flushing process was repeated twice more. The reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×25 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) followed by flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 70:30 over 20 column volumes and held for 4 column volumes; increased to 25:75 over 10 column volumes) followed by trituration in hot EtOH provided the title compound (19 mg, 7%) as an off-white powder: mp 178-181° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.53 (t, J=5.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.00 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.21-3.10 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), 2.08-2.07 (m, 2H); ESI MS m/z 414 [M+H]⁺; HPLC (Method A) 97.2% (AUC), t_(R)=16.5 min.

Example 39 Preparation of 5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridazin-3(2H)-one hydrochloride

a) tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.31 g, 0.82 mmol), 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (0.20 g, 0.91 mmol), and Cs₂CO₃ (0.35 g, 1.1 mmol) were suspended in DMSO (5.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and the process was repeated. 8-Hydroxyquinoline (36 mg, 0.25 mmol) and copper iodide (0.39 g, 2.1 mmol) were added to the suspension, the evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under positive N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq)/NH₄OH/H₂O (40 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ and washed with 5.0:3.5:1.5 NH₄Cl (aq)/NH₄OH/H₂O (3×30 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (40 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) provided the title compound (83 mg, 19%) as a yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (d, J=3.0 Hz, 1H), 7.97 (d, J=3.0 Hz, 1H), 7.84-7.82 (m, 1H), 7.70 (dd, J=9.0, 4.5 Hz, 1H), 7.49-7.47 (m, 2H), 7.05 (d, J=9.0 Hz, 1H), 6.52 (d, J=2.0 Hz, 1H), 5.29 (s, 2H), 4.59-4.57 (m, 2H), 3.66-3.65 (m, 5H), 2.99-298 (m, 2H), 1.94-1.90 (m, 2H), 1.36-1.27 (m, 9H).

b) 5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridazin-3(2H)-one hydrochloride

tert-Butyl-8-(4-(5-fluoropyridin-2yl)methoxy)-6-oxopyridazin-1(6H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (83 mg, 0.16 mmol) was treated with 1.25 M HCl in MeOH (9.5 mL) and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with Et₂O and the resulting solids were collected by filtration to provide the title compound (62 mg, 85%) as a light brown powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 2H), 8.63 (d, J=2.5 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.87-7.83 (m, 1H), 7.72-7.69 (m, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.5, 1.5 Hz, 1H), 6.52 (d, J=3.0 Hz, 1H), 5.29 (s, 2H), 4.44-4.43 (m, 2H), 3.72 (s, 3H), 3.45-3.43 (m, 2H), 3.10 (t, J=5.5 Hz, 2H), 2.07-2.05 (m, 2H); ESI MS m/z 420 [M+H]⁺; HPLC (Method A) 97.7% (AUC), t_(R)=12.3 min.

Example 40 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl-8-(4-((5-(fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (0.15 g, 0.39 mmol), 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (0.13 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (4×20 mL). The solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) provided the title compound (0.17 g, 52%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (d, J=2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.63 (m, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 6.89 (dd, J=8.5, 2.0 Hz, 1H), 6.11 (dd, J=7.5, 3.0 Hz, 1H), 5.95 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 3.68-3.64 (m, 5H), 3.58-3.57 (m, 2H), 3.02-3.01 (m, 2H), 2.94-2.93 (m, 2H), 1.43-1.42 (m, 9H); ESI MS m/z 519 [M+H]⁺.

b) 4-((5-Fluoropyridin-2-yl)methoxy-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl-8-(4-((5-(fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (0.10 g, 0.12 mmol) in 1.25 M HCl in MeOH (26 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness under reduced pressure and diluted with MeOH (2.0 mL) and Et₂O (20 mL). The resulting solids were collected by filtration and dried to provide the title compound (78 mg, 87%) as a yellow powder: mp 194-202° C. decomp; ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (s, 2H), 8.62 (d, J=3.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.56 (dd, J=7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.42 (s, 1H), 6.94 (dd, J=8.5, 1.5 Hz, 1H), 6.12 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.12 (s, 2H), 3.68 (s, 3H), 3.37-3.32 (m, 4H), 3.26-3.25 (m, 2H), 3.13-3.12 (m, 2H); ESI MS m/z 419 [M+H]⁺; HPLC (Method A) 98.0% (AUC), t_(R)=12.5 min.

Example 41 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridin-1(2H)-yl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (0.15 g, 0.39 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (0.12 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and washed with brine (3×20 mL). The organic solution was dried over Na₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (81 mg, 38%) as a yellow film: ¹H NMR (300 MHz, DMSO-d₆) δ 7.99 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.77 (d, J=6.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 6.98 (dd, J=8.1, 1.5 Hz, 1H), 6.84 (d, J=1.8 Hz, 1H), 6.69 (dd, J=7.2, 2.1 Hz, 1H), 3.65-3.57 (m, 7H), 3.01-2.94 (m, 4H), 1.15 (s, 9H); ESI MS m/z 538 [M+H]⁺.

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochloride

tert-Butyl 6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridin-1(2H)-yl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (73 mg, 0.14 mmol) in 1.25 M HCl in MeOH (18 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness and diluted with MeOH (2.0 mL) and Et₂O (20 mL). The resulting solids were collected by filtration and dried to yield the title compound (44 mg, 74%) as a yellow powder: mp 306-310° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.29 (s, 2H), 8.00 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.79 (d, J=7.0 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.55 (d, J=1.0 Hz, 1H), 7.05 (dd, J=8.5, 1.5 Hz, 1H), 6.86 (d, J=1.5 Hz, 1H), 6.71 (dd, J=7.0, 2.0 Hz, 1H), 3.71 (s, 3H), 3.39-3.33 (m, 4H), 3.28-3.27 (m, 2H), 3.16-3.13 (m, 2H); ESI MS m/z 438 [M+H]⁺; HPLC (Method A) 99.4% (AUC), t_(R)=15.3 min.

Example 42 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one hydrochloride

a) tert-Butyl-8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl-8-(4-((5-fluoropyridin-2-yl)methoxy-2-oxopyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (0.31 g, 0.82 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.15 g, 0.68 mmol), and Cs₂CO₃ (0.24 g, 0.75 mmol) were suspended in DMSO (5.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar and 8-hydroxyquinoline (20 mg, 0.14 mmol) and copper iodide (0.16 g, 0.82 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl(aq.)/NH₄OH/H₂O (40 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂(50 mL) and washed with 5.0:3.5:1.5 NH₄Cl(aq.)/NH₄OH/H₂O (40 mL) (2×30 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) provided the title compound (0.15 g, 34%) as a yellow film: ¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 7.66-7.63 (m, 2H), 7.52-7.45 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.26-7.22 (m, 3H), 6.12 (dd, J=7.5, 2.5 Hz, 1H), 6.06 (d, J=3.0 Hz, 1H), 5.18 (s, 2H), 3.67-3.62 (m, 4H), 3.36-3.34 (m, 2H), 2.94-2.90 (m, 2H), 2.34 (s, 3H), 1.46-1.44 (m, 9H).

b) tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H))-carboxylate

NaOH (1.2 g, 30 mmol) was added to a solution of tert-butyl-8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (0.15 g, 0.23 mmol) in 1:1 CH₂Cl₂/MeOH (14 mL), and the resulting solution was stirred at ambient temperature for 18 h. The mixture was diluted with H₂O and extracted with CH₂Cl₂ (3×25 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to dryness. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 25:75 over 20 column volumes and held for 12 column volumes) provided the title compound (84 mg, 72%) as an off-white film: ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.62 (d, J=3.0 Hz, 1H), 7.83-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 6.85 (dd, J=8.0, 1.5 Hz, 1H), 6.09 (dd, J=8.0, 3.0 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 3.59-3.57 (s, 4H), 2.96-2.94 (m, 2H), 2.88-2.86 (m, 2H), 1.43 (s, 9H).

c) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one

tert-Butyl 8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H))-carboxylate (80 mg, 0.16 mmol) was treated with 1.25 M HCl in MeOH (7.5 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was concentrated to dryness to provide the title compound (100 mg, quantitative) as a brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.21 (s, 1H), 9.32 (s, 2H), 8.62 (s, 1H), 7.85-7.80 (m, 1H), 7.67-7.63 (m, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.50-7.47 (m, 1H), 7.24 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.12-6.07 (m, 1H), 5.96-5.95 (m, 1H), 5.21 (s, 2H), 3.34-3.32 (m, 4H), 3.19-3.16 (m, 2H), 3.11-3.09 (m, 2H).

d) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one

AcOH (0.42 mL) and picoline borane complex (51 mg, 0.47 mmol) were added to 4-((5-fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one (69 mg, 0.16 mmol) suspended in 1:1 CH₂Cl₂/acetone (4.8 mL), and the resulting suspension was heated at reflux for 68 h. Additional acetone (1.0 mL) and picoline borane complex (20 mg, 19 mmol) were added, and the resulting suspension heated at reflux for 68 h. The reaction was cooled and concentrated to dryness under reduced pressure. 1 N HCl (10 ml) was added, and the suspension stirred at ambient temperature for 2 h. The mixture was made basic with 1 N NaOH and extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Preparative TLC (Analtech, 20×20 cm, 1000 microns, 80:18:2 CH₂Cl₂/MeOH/NH₄OH) provided the title compound (31 mg, 43%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.61 (d, J=2.5 Hz, 1H), 7.82-7.81 (m, 1H), 7.66-7.63 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.14 (s, 1H), 6.82 (d, J=7.0 Hz, 1H), 6.09 (dd, J=7.5, 3.0 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 3.02-2.98 (m, 1H), 2.86-2.85 (m, 2H), 2.76 (m, 6H), 1.02 (d, J=6.5 Hz, 6H); ESI MS m/z 447 [M+H]⁺.

e) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one hydrochloride

1.25 M HCl in MeOH (48 μL, 0.060 mmol) was added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one (27 mg, 0.060 mmol) in MeOH (2.0 mL), and the resulting solution was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness to provide the title compound (26 mg, 90%) as an off-white powder: ESI MS m/z 447 [M+H]⁺; HPLC (Method A) 97.6% (AUC), t_(R)=12.7 min.

Example 43 Preparation of 4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (80 mg, 0.33 mmol) and Cs₂CO₃ (390 mg, 0.38 mmol) were suspended in DMSO (8.0 mL) and degassed under vacuum for 15 min. The system was then flushed with Ar, and 8-hydroxyquinoline (30 mg, 0.18 mmol) and copper iodide (80 mg, 0.40 mmol) were added. The degassing/Ar flushing process was repeated twice, and the reaction mixture was heated to 133° C. for 18 h under argon. The mixture was cooled, diluted with 17:3 MeOH/NH₄OH (25 mL) and stirred at ambient temperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL). The solution was filtered through silica gel and concentrated under reduced pressure. The residue was diluted with CH₂Cl₂. The resulting solution was washed with H₂O (2×25 mL) and brine (3×50 mL). The combined organics were dried over Na₂SO₄, filtered and concentrated under reduced pressure to dryness. Flash chromatography purification (silica gel, (A=1:1 hexanes/EtOAc)/B=10:1:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) provided a white solid. TFA (2 mL) was added to a solution of the white solid in 1:1 MeOH/CH₂Cl₂, and the resulting mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure, and the residue was neutralized by ion-exchange chromatography (SCX-2 column, 2 g). Preparative TLC (silica gel, 10:1:0.1 CH₂Cl₂/MeOH/NH₄OH) provided a white foam. The white foam was dissolved in methanol (5 mL) and treated with 1.25 M HCl in MeOH (0.3 mL). The resulting solution was stirred for 5 min at ambient temperature. The mixture was concentrated, and the resulting residue was lyophilized from water (5 mL) to afford the title compound (58 mg, 18%) as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (br s, 2H), 7.55-7.37 (m, 8H), 6.94 (dd, J=8.0, 1.0 Hz, 1H), 6.09 (dd, J=9.0 Hz, 1.0, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.36-3.26 (m, 6H), 3.14-3.12 (m, 2H); ESI MS m/z 400 [M+H]⁺; HPLC (Method A) 97.9% (AUC), t_(R)=14.4 min.

Example 44 Preparation of 4-(benzyloxy)-1-(3,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

To a solution of 4-(benzyloxy)-1-(3,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one (270 mg, 0.65 mmol) in 99:1 CH₂Cl₂/AcOH (10 mL) were added formaldehyde (38% solution in water, 100 μL, 1.3 mmol), and NaBH(OAc)₃ (550 mg, 2.6 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The mixture was concentrated, and the residue was dissolved in CH₂Cl₂. The organic layer was washed with brine, water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. Flash chromatography (silica gel, (A=dichloromethane, B=10:1:0.1 CH₂Cl₂/MeOH/NH₄OH, 100:0 to 0:100), followed by purification by preparative TLC (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) provided a white solid (58 mg). The white solid was dissolved in methanol (5 mL) and treated with 1.25 M HCl in MeOH (1 mL). The resulting solution was stirred for 5 min at ambient temperature. The mixture was concentrated, and the resulting residue was lyophilized from water (5 mL) to afford the title compound (48 mg, 16%) as a white powder: ¹H NMR (500 MHz, CD₃OD) δ 7.58 (dd, J=8.5 Hz, 3.0 Hz, 2H), 7.46 (dd, J=8.0 Hz, 2.0 Hz, 2H), 7.43-7.39 (m, 3H), 7.37-7.35 (m, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.31 (dd, J=7.5, 2.5 Hz, 1H), 6.13 (d, J=1.5 Hz, 1H), 5.18 (s, 2H), 3.81-3.75 (m, 2H), 3.73 (s, 3H), 3.60-3.42 (m 2H), 3.41-3.32 (m, 2H); 3.20-3.10 (m, 2H), 3.08 (s, 3H); ESI MS m/z 414 [M+H]⁺; HPLC (Method A) 99.8% (AUC), t_(R)=14.2 min.

Example 45 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one dihydrochloride

A suspension of 4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one (82 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (158 mg, 0.42 mmol), CuI (87 mg, 0.46 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and Cs₂CO₃ (136 mg, 0.42 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 8 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded an off-white solid. 1.25 N HCl in MeOH (5 mL) was added to the off-white solid under N₂, and the resulting suspension was stirred at 25° C. for 18 h. The suspension was concentrated, and the residue was freeze dried to afford the title compound (105 mg, 57%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.23 (br s, 2H), 8.81 (s, 1H), 8.40-8.25 (m, 1H), 7.82-7.75 (m, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.42 (d, J=2.0, 1H), 6.94 (dd, J=8.5, 2.0 Hz, 1H), 6.12 (dd, J=8.0, 3.0 Hz, 1H), 6.02 (d, J=2.5 Hz, 1H), 5.28 (s, 2H), 3.69 (s, 3H), 3.41-3.29 (m, 4H), 3.28-3.22 (m, 2H), 3.15-3.10 (m, 2H), 2.68 (s, 3H); ESI MS m/z 415 [M+H]⁺.

Example 46 Preparation of 1-(3-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one

A suspension of 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (2.21 g, 5.83 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (1.54 g, 6.41 mmol), CuI (1.33 g, 6.99 mmol), 8-hydroxyquinoline (169 mg, 1.17 mmol) and Cs₂CO₃ (2.09 g, 6.41 mmol) in DMSO (30 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 15 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a yellow solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the yellow solid in 1:1 CH₂Cl₂/MeOH (2 mL) under N₂, and the resulting suspension was stirred at 25° C. for 19 h. The suspension was filtered and the solid was washed with Et₂O, CH₂Cl₂, and Et₂O in succession. The material was dried in a vacuum oven at 60° C. for 3 d to afford 1.70 g of a yellow solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) of 184 mg of the yellow solid afforded 59 mg of a yellow solid. AcCl (0.02 mL, 0.20 mmol) was added to a solution of the yellow solid, DMAP (3 mg, 0.03 mmol) and Et₃N (0.04 mL, 0.27 mmol) in CH₂Cl₂ (20 mL) under N₂, and the resulting solution was stirred at 25° C. for 2 h. The reaction solution was concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 61 mg (20%) of the title compound as a yellow powder as a mixture of rotomers: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.84 (d, J=7.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.53-7.50 (m, 1H), 7.04-6.99 (m, 2H), 6.79 (dd, J=7.0, 2.0 Hz, 1H), 3.85-3.65 (m, 7H), 3.14-2.93 (m, 4H), 2.14 (s, 1.2H), 2.09 (s, 1.8H); ESI MS m/z 481 [M+H]⁺.

Example 47 Preparation of 2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one hydrochloride

a) 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (CAS Registry Number 1008517-74-5) (WO 2008/022979 to Stenkamp et al., which is hereby incorporated by reference in its entirety)

This compound was prepared in accordance with the procedure of Stenkamp et al., WO 2008/022979, which is hereby incorporated by reference in its entirety.

b) 2-(Tetrahydro-2H-pyran-2-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one

5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.3 g, 12 mmol), 5-(bromomethyl)-2-(trifluoromethyl)pyridine (7.2 g, 30 mmol) and K₂CO₃ (8.4 g, 60 mmol) were stirred in DMF (40 ml) and CH₂Cl₂ (40 ml) for 48 h. The mixture was diluted with CH₂Cl₂, washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (5.25 g, >100%) as a waxy white solid containing some DMF: ¹H NMR (300 MHz, CDCl₃) δ 8.78 (d, J=1.8 Hz, 1H), 7.97-7.88 (m, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.72 (m, 1H), 6.20 (d, J=2.9 Hz, 1H), 6.03-5.98 (d, J=10.9, 2.0 Hz, 1H), 5.11 (s, 2H), 4.16-4.08 (m, 1H), 3.79-3.69 (m, 1H), 2.24-1.96 (m, 2H), 1.83-1.48 (m, 4H).

c) 5-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one

2-(Tetrahydro-2H-pyran-2-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (5.25 g, 12 mmol estimated) was stirred in MeOH (10 mL), and 2 N HCl in Et₂O (50 mL) was added. After 16H, the mixture was diluted with Et₂O (100 mL), and the solid was filtered off. The solid was stirred in NaHCO₃ solution (15 mL) for 15 minutes and then refiltered to provide the title compound (2.2 g, 67%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.74 (s, 1H), 8.78 (s, 1H), 8.20-8.16 (dd, J=8.1, 1.5 Hz, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.76 (d, J=2.6 Hz, 1H), 6.31 (s, 1H), 5.25 (s, 2H).

d) 2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one hydrochloride

A suspension of 5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (140 mg, 0.519 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (164 mg, 0.433 mmol), CuI (99 mg, 0.52 mmol), 8-hydroxyquinoline (13 mg, 0.087 mmol) and Cs₂CO₃ (155 mg, 0.476 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 40 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded an off-white solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the off-white solid in 1:1 CH₂Cl₂/MeOH (2 mL) under N₂, and the resulting suspension was stirred at 25° C. for 19 h. The suspension was filtered, and the solid was washed with Et₂O to afford 42 mg (19%) of the title compound as an off-white solid: mp 270-274° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.02-8.91 (m, 3H), 8.23 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.00 (d, J=2.5, 1H), 7.55-7.51 (m, 2H), 7.09 (dd, J=8.5, 2.0 Hz, 1H), 6.56 (d, J=3.0 Hz, 1H), 5.42 (s, 2H), 3.69 (s, 3H), 3.44-3.28 (m, 4H), 3.27-3.21 (m, 2H), 3.13-3.09 (m, 2H); ESI MS m/z 470 [M+H]⁺.

Example 48 Preparation of 1-(3-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one

AcCl (0.01 mL, 0.2 mmol) was added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (49 mg, 0.11 mmol), DMAP (3 mg, 0.03 mmol), and Et₃N (0.03 mL, 0.3 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirred at 25° C. for 4 h. H₂O was added and the resulting phases were separated. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 39 mg (78%) of the title compound as a white solid as a mixture of rotomers: mp 88-94° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 7.84 (ddd, J=9.0, 9.0, 3.0 Hz, 1H), 7.66 (dd, J=8.5, 4.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.38 (dd, J=3.0, 1.5 Hz, 1H), 6.92-6.88 (m, 1H), 6.12 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.22 (s, 2H), 3.82-3.76 (m, 2H), 3.75-3.63 (m, 5H), 3.10 (t J=5.5, 1H), 3.05-2.98 (m, 2H), 2.93 (t, J=5.5, 1H), 2.13 (s, 1.5H), 2.08 (s, 1.5H); ESI MS m/z 461 [M+H]⁺.

Example 49 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoromethyl)phenyl)pyrimidin-2(1H)-one hydrochloride

a) 4-(4-(Trifluoromethyl)phenyl)pyrimidin-2(1H)-one (CAS Registry Number 1159816-20-2)

A suspension of 4-chloro-2-methoxypyrimidine (500 mg, 3.47 mmol), 4-(trifluoromethyl)phenylboronic acid (788 mg, 4.17 mmol), PdCl₂(dppf) (283 mg, 0.347 mmol) and K₂CO₃ (958 mg, 6.94 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 95° C. for 20 h. The suspension was cooled, H₂O was added and the suspension was filtered to afford a light colored solid. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. The white solid was diluted with concentrated HCl solution (10 mL) and stirred at reflux for 4 h. The reaction was cooled, and the solution was neutralized with saturated NaHCO₃ solution. The resulting suspension was filtered to afford 185 mg (22%) of the title compound as a white solid: ESI MS m/z 241 [M+H]⁺.

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoromethyl)phenyl)pyrimidin-2(1H)-one hydrochloride

A suspension of 4-(4-(trifluoromethyl)phenyl)pyrimidin-2(1H)-one (72 mg, 0.30 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (136 mg, 0.358 mmol), CuI (68 mg, 0.36 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs₂CO₃ (107 mg, 0.329 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 17 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a yellow solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the yellow solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 15 h. The suspension was filtered, and the solid was washed with 9:1 CH₂Cl₂/MeOH and Et₂O in succession to afford 53 mg (37%) of the title compound as an orange solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 8.40 (d, J=8.0 Hz, 2H), 8.38 (d, J=7.0 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.65 (d, J=1.5, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.27 (d, J=7.0 Hz, 1H), 7.14 (dd, J=8.0, 1.5 Hz, 1H), 3.72 (s, 3H), 3.43-3.32 (m, 4H), 3.29-3.24 (m, 2H), 3.16-3.12 (m, 2H); ESI MS m/z 439 [M+H]⁺.

Example 50 Preparation of 4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 4((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide (CAS Registry Number 1039826-88-4) (WO 2008/086404 to Guzzo et al., which is hereby incorporated by reference in its entirety)

5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and 4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (2.2 g, 40%) as a tan solid: ¹H NMR (300 MHz, CDCl₃) δ 8.58 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 2H), 7.74 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).

b) 4((5-Chloropyridin-2-yl)methoxy)pyridin-2 (1H)-one (CAS Registry Number 924311-89-7) (WO 2007/018248 to Ando et al., which is hereby incorporated by reference in its entirety)

4-((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide (2.2 g, 9.2 mmol) was reacted according to Example 34 (step b) to provide the title compound (1.52 g, 69%) as a tan solid: ¹H NMR (500 MHz, CD₃OD) δ 8.56 (d, J=2.3 Hz, 1H), 7.91-7.89 (dd, J=8.4, 2.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 6.21-6.19 (dd, J=7.2, 2.5 Hz, 1H), 5.97 (d, J=2.4 Hz, 1H), 5.18 (s, 2H).

c) 4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (116 mg, 0.489 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (204 mg, 0.538 mmol), CuI (111 mg, 0.587 mmol), 8-hydroxyquinoline (14 mg, 0.10 mmol) and Cs₂CO₃ (175 mg, 0.381 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 19 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) afforded a tan solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the tan solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 15 h. The suspension was filtered, and the solid was washed with Et₂O and freeze dried to afford 82 mg (36%) of the title compound as a light yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.78 (d, J=2.5 Hz, 1H), 8.03 (dd, J=8.5, 2.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 6.94 (dd, J=8.0, 1.5 Hz, 1H), 6.14 (dd, J=7.5, 3.0 Hz, 1H), 5.95 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.69 (s, 3H), 3.40-3.30 (m, 4H), 3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H); ESI MS m/z 435 [M+H]⁺.

Example 51 Preparation of 4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one

a) 4-(2,4-Dichlorobenzyloxy)pyridin-2(1H)-one (CAS Registry Number 1182243-20-4) (WO 2007/043,835 to Kim et al., which is hereby incorporated by reference in its entirety)

A suspension of (2,4-dichlorophenyl)methanol (4.10 g, 23.2 mmol), 2-chloro-4-iodopyridine (5.05 g, 21.1 mmol), Cs₂CO₃ (8.94 g, 27.4 mmol), CuI (4.01 g, 21.1 mmol) and 1,10-phenanthroline (760 mg, 4.22 mmol) in toluene (20 mL) was degassed by bubbling N₂ through the suspension for 15 min. The suspension was put under N₂, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO₂. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH₄OAc (6.13 g, 79.5 mmol) in 1:1 HCO₂H/H₂O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO₃ solution and the resulting suspension was filtered. The solid was washed with H₂O and dried under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 1.36 g (24%) of the title compound as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.16 (br s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.61 (d, J=8.1, 1H), 7.50 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.91 (dd, J=7.5, 2.7 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.10 (s, 2H).

b) 4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one

A suspension of 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (103 mg, 0.381 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (131 mg, 0.347 mmol), CuI (79 mg, 0.42 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and Cs₂CO₃ (124 mg, 0.381 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 48 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄, and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH), 100:0 to 0:100) afforded a tan solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the tan solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 17 h. The suspension was filtered, and the solid was washed with Et₂O and freeze dried to afford 66 mg (38%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.74 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.54-7.50 (m, 2H), 7.45 (d, J=1.5 Hz, 1H), 6.96 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 3.0 Hz, 1H), 6.00 (d, J=3.0 Hz, 1H), 5.19 (s, 2H), 3.69 (s, 3H), 3.42-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H); ESI MS m/z 468 [M+H]⁺.

Example 52 Preparation of 4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 4-(2,4-Difluorobenzyloxy)pyridin-2(1H)-one (CAS Registry Number 586373-58-2) (WO 2003/068230 to Devadas et al., which is hereby incorporated by reference in its entirety)

A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs₂CO₃ (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was degassed by bubbling N₂ through the suspension for 15 min. The suspension was put under N₂, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO₂. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH₄OAc (8.21 g, 107 mmol) in 1:1 HCO₂H/H₂O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO₃ solution, and the resulting suspension was filtered. The solid was washed with H₂O and dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).

b) 4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (114 mg, 0.479 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (165 mg, 0.435 mmol), CuI (99 mg, 0.52 mmol), 8-hydroxyquinoline (13 mg, 0.087 mmol) and Cs₂CO₃ (156 mg, 0.479 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 2 d. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄, and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded a yellow residue. 2 N HCl in Et₂O (100 mL) was added to a solution of the yellow residue in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 45° C. for 2 h to afford 98 mg (48%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.67 (dd, J=15.0, 9.0 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.35 (ddd, J=10.5, 10.5, 2.0 Hz, 1H), 7.18 (ddd, J=8.5, 8.5, 2.5 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 6.04 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 3.69 (s, 3H), 3.41-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.14-3.10 (m, 2H); ESI MS m/z 436 [M+H]⁺.

Example 53 Preparation of 4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-one dihydrochloride

a) 4-(4-Chlorophenethyl)piperazin-2-one

Piperazinone (1.04 g, 10.4 mmol), 1-chloro-4-(2-chloroethyl)benzene (2.28 g, 10.4 mmol) and K₂CO₃ (1.72 g, 12.4 mmol) were combined in DMSO (12 mL) and heated to 85° C. for 2 h. The mixture was partitioned between H₂O (20 mL) and CH₂Cl₂ (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH₂Cl₂ (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH₂Cl₂ (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH₂Cl₂ (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.51 g, 60%) as an orange solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 3.14-3.10 (m, 2H), 2.96 (s, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.62-2.53 (m, 4H).

b) 4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-one dihydrochloride

A suspension of 4-(4-chlorophenethyl)piperazin-2-one (90 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (130 mg, 0.344 mmol), Cs₂CO₃ (123 mg, 0.378 mmol), CuI (131 mg, 0.688 mmol) and trans-1,2-bis(methylamino)cyclohexane (24 mg, 0.17 mmol) in dioxane (10 mL) was degassed by bubbling N₂ through the suspension for 45 min. The suspension was put under N₂ and heated at reflux for 5 d. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded tert-butyl 8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate as a tan solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the tan solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 16 h. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et₂O (100 mL) was added, the resulting suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 40° C. for 1 h to afford 22 mg (13%) of the title compound as a tan solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (br s, 1H), 9.16 (br s, 2H), 7.54-7.32 (m, 6H), 6.96 (d, J=8.0 Hz, 1H), 4.21-3.44 (m, 9H), 3.42-3.05 (m, 12H); ESI MS m/z 437 [M+H]⁺.

Example 54 Preparation of 1-(3-Acetyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(benzyloxy)pyridin-2(1H)-one

AcCl (0.03 mL, 0.4 mmol) was added to a solution of 4-(benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (102 mg, 0.242 mmol), DMAP (6 mg, 0.05 mmol) and Et₃N (0.10 mL, 0.73 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resulting solution was stirred at 25° C. for 4 h. The solution was concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded 35 mg (34%) of the title compound as an off-white solid: mp 250-254° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.19 (dd, J=2.5, 2.5 Hz, 1H), 6.88-6.83 (m, 1H), 6.07 (dd, J=8.0, 2.5 Hz, 1H), 5.95 (d, J=2.5, 1H), 5.14 (s, 2H), 3.76-3.65 (m, 4H), 3.06-3.02 (m, 1H), 2.97-2.91 (m, 2H), 2.87-2.82 (m, 1H), 2.12 (s, 3H); ESI MS m/z 428 [M+H]⁺.

Example 55 Preparation of 4-(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 4-(4-Chloro-2-fluorobenzyloxy)pyridin-2(1H)-one

A suspension of (4-chloro-2-fluorophenyl)methanol (3.24 g, 20.1 mmol), 2-chloro-4-iodopyridine (4.40 g, 18.3 mmol), Cs₂CO₃ (7.76 g, 23.8 mmol), CuI (3.48 g, 18.7 mmol) and 1,10-phenanthroline (659 mg, 3.66 mmol) in toluene (20 mL) was degassed by bubbling N₂ through the suspension for 15 min. The suspension was put under N₂ and heated at 105° C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was passed through a plug of SiO₂. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH₄OAc (2.66 g, 34.6 mmol) in 1:1 HCO₂H/H₂O (20 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO₃ solution, and the resulting suspension was filtered. The solid was washed with H₂O and CH₂Cl₂, and dried under reduced pressure to afford 1.28 g (28%) of the title compound as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (br s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.52 (dd, J=10.2, 1.8 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 5.89 (d, J=7.2, 2.4 Hz, 1H), 5.83 (d, J=2.4 Hz, 1H), 5.06 (s, 2H).

b) 4-(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (87 mg, 0.34 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (143 mg, 0.380 mmol), CuI (78 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg, 0.068 mmol) and Cs₂CO₃ (124 mg, 0.38 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 22 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄, and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded an off-white powder. 2 N HCl in Et₂O (100 mL) was added to a solution of the yellow residue in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 22 h. The suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 40° C. for 2 h to afford 48 mg (29%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (br s, 2H), 7.63 (dd, J=8.0, 8.0 Hz, 1H), 7.57-7.50 (m, 3H), 7.43 (d, J=1.5 Hz, 1H), 7.39 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.08 (dd, J=7.5, 3.0 Hz, 1H), 6.02 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 3.69 (s, 3H), 3.41-3.31 (m, 4H), 3.28-3.22 (m, 2H), 3.16-3.09 (m, 2H); ESI MS m/z 452 [M+H]⁺.

Example 56 Preparation of 4-((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 3,5-Dichloro-2-((2-chloropyridin-4-yloxy)methyl)pyridine

(3,5-Dichloropyridin-2-yl)methanol (2.00 g, 10.4 mmol), 2-chloro-4-iodopyridine (2.49 g, 10.4 mmol), cesium carbonate (4.41 g, 13.5 mmol), CuI (1.97 g, 10.4 mmol) and 1,10-phenanthroline (374 mg, 2.08 mmol) were stirred in toluene (20 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed to cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the resulting residue was purified by column chromatography (80 g ISCO column column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 40% ethyl acetate) to provide the title compound (1.15 g, 38%) as an orange solid: ¹H NMR (300 MHz, CDCl₃) δ 8.50 (d, J=2.1 Hz, 1H), 8.21 (d, J=5.8 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.88-6.85 (dd, J=5.8, 2.2 Hz, 1H), 5.31 (s, 2H).

b) 4((3,5-Dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one

3,5-Dichloro-2-((2-chloropyridin-4-yloxy)methyl)pyridine (1.15 g, 4.03 mmol) and ammonium acetate (1.55 g, 20.0 mmol) were heated to 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO₃ solution. The solid was filtered off to provide the title compound (910 mg, 82%) as a tan solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.1 (br s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 5.90-5.87 (dd, J=7.3, 2.8 Hz, 1H), 5.82 (d, J=2.6 Hz, 1H), 5.20 (s, 2H).

c) 4((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-((3,5-dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one (103 mg, 0.380 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (131 mg, 0.345 mmol), Cs₂CO₃ (124 mg, 0.380 mmol), CuI (79 mg, 0.41 mmol) and trans-1,2-bis(methylamino)cyclohexane (33 mg, 0.23 mmol) in toluene (10 mL) was degassed by bubbling N₂ through the suspension for 45 min. The suspension was put under N₂ and heated at reflux for 2 d. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded a viscous oil. 2 N HCl in Et₂O (100 mL) was added to a solution of the viscous oil in CH₂Cl₂ (10 mL) under N₂, and the resulting suspension was stirred at 25° C. for 16 h. The suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 40° C. for 3 h to afford 59 mg (34%) of the title compound as a white powder: mp 178-180° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.69 (s, 1H), 8.37 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.09 (dd, J=7.5, 2.5 Hz, 1H), 6.01 (s, 1H), 5.30 (s, 2H), 3.69 (s, 3H), 3.42-3.30 (m, 4H), 3.28-3.22 (m, 2H), 3.17-3.09 (m, 2H); ESI MS m/z 469 [M+H]⁺.

Example 57 Preparation of 4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 2-Chloro-4-(4-fluorobenzyloxy)pyridine (CAS Registry Number 924311-93-3) (WO 2007/018248 to Ando et al., which is hereby incorporated by reference in its entirety)

A mixture of 2-chloro-4-iodopyridine (5.0 g, 21 mmol), 4-fluorobenzyl alcohol (2.51 mL, 23.0 mmol), cesium carbonate (8.9 g, 27 mmol), CuI (4.0 g, 21 mmol) and phenanthronine (0.76 g, 4.2 mmol) in toluene (20 mL) was purged with nitrogen for 10 min. The reaction mixture was heated at 105° C. overnight. The resulting mixture was cooled, diluted with EtOAc, and the resulting solution was washed with brine, passed through a pad of celite and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (hexanes/EtOAc 100% to 85%) to give the title compound as a mixture with 4-fluorobenzyl alcohol (3.9 g, mixture), which was used in next step without further purification: ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J=6.0 Hz, 1H), 7.38 (dd, J=8.5, 5.5 Hz, 2H), 7.10 (t, J=8.5 Hz, 2H), 6.90 (d, J=2.0 Hz, 1H), 6.80 (dd, J=5.5, 2.0 Hz, 1H), 5.06 (s, 2H).

b) 4-(4-Fluorobenzyloxy)pyridin-2(1H)-one (CAS Registry Number 586373-38-8) (WO 2003/068230 to Devadas et al., which is hereby incorporated by reference in its entirety)

A mixture of 2-chloro-4-(4-fluorobenzyloxy)pyridine (3.9 g, mixture) and ammonium acetate (4.2 g, 55 mmol) in formic acid (20 mL, 90% in water) and water (20 mL) was heated under reflux for 6 days. The resulting mixture was concentrated under reduced pressure, triturated with EtOAc and filtered. The resulting filtrate was concentrated under reduced pressure and purified by flash column chromatography (hexanes/EtOAc 17% to 50%; then DCM/MeOH/concentrated ammonia 80:18:2) to give the title compound (0.80 g, 17%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 12.61-2.32 (br s, 1H), 7.38 (dd, J=8.5, 5.5 Hz, 2H), 7.22 (d, J=7.5 Hz, 1H), 7.09 (t, J=8.5 Hz, 2H), 6.03 (dd, J=7.5, 2.5 Hz, 1H), 5.95 (d, J=2.5 Hz, 1H), 4.98 (s, 2H).

c) tert-Butyl 8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)carboxylate

A suspension of 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (79 mg, 0.36 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (150 mg, 0.40 mmol), 8-hydroxyquinoline (11 mg, 0.072 mmol) and Cs₂CO₃ (129 mg, 0.40 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (82 mg, 0.43 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 2×5 min. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. Purification by preparative TLC (DCM/MeOH/concentrated ammonia 98:1.8:0.2) gave partially purified product, which was dissolved in DCM and stirred with charcoal for 10 min. The suspension was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (0.12 g, 64%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.52 (t, J=8.0 Hz, 1H), 7.41 (dd, J=8.5, 5.5 Hz, 2H), 7.31 (d, J=7.5 Hz, 1H), 7.24 (s, 1H), 7.10 (t, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.07 (s, 1H), 6.02 (dd, J=7.5, 2.0 Hz, 1H), 5.01 (s, 2H), 3.78-3.63 (m, 4H), 3.64 (s, 3H), 3.05-2.98 (m, 4H), 1.50-1.48 (m, 9H).

d) 4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

To a solution of tert-butyl 8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (120 mg, 0.23 mmol) in dichloromethane (1.0 mL) was added HCl (2M in diethyl ether, 5.0 mL). The resulting slurry was stirred at room temperature overnight and concentrated under reduced pressure to afford the title compound (85 mg, 82%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 7.59 (d, J=8.5 Hz, 2H), 7.50 (dd, J=8.0, 5.5 Hz, 2H), 7.40 (s, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.01 (d, J=8.5 Hz, 1H), 6.30 (t, J=6.5 Hz, 1H), 6.14 (br s, 1H), 5.16 (s, 2H), 3.74 (s, 3H), 3.54 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.34 (t, J=5.5 Hz, 2H), 3.24 (t, J=5.5 Hz, 2H); ESI MS m/z 418 [M+H]⁺.

Example 58 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one hydrochloride

a) 2-Methoxy-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine

A solution of 4-chloro-2-methoxypyrimidine (0.50 g, 3.5 mmol), 2-trifluoromethyl)pyridine-5-boronic acid (1.0 g, 5.2 mmol) and potassium carbonate (0.95 g, 6.9 mmol) in DMSO was degassed with argon for 10 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.26 g, 0.35 mmol) was then added to the above solution. The reaction mixture was degassed with argon for 5 min and then heated at 100° C. for 4 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water (2×) and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel hexanes/ethyl acetate 95:5 to 50:50) to afford the title compound (0.80 g, 90%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.69 (d, J=5.5 Hz, 1H), 8.61 (dd, J=8.0, 2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.44 (d, J=5.0 Hz, 1H), 4.12 (s 3H).

b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one

A solution of 2-methoxy-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine (0.35 g, 1.37 mmol) in concentrated HCl (3.0 mL) was heated under reflux for 16 h. The reaction solution was then cooled to 0° C., diluted with water and basified with aqueous sodium hydroxide. The mixture was then extracted with dichloromethane (2×), a 3:1 mixture of chloroform and 2-propanol (3×), ethyl acetate (4×) and ethyl acetate with 5% methanol (3×). The combined organic extract was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (0.25 g, 75%) as a tan solid: ¹H NMR (500 MHz, CD₃OD) δ 9.34 (s, 1H), 8.67 (d, J=8.5 Hz, 1H), 8.20 (d, J=6.0 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.08 (d, J=5.5 Hz, 1H).

c) tert-Butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one (69 mg, 0.29 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (120 mg, 0.32 mmol), 8-hydroxyquinoline (8.4 mg, 0.058 mmol) and Cs₂CO₃ (110 mg, 0.35 mmol) in DMSO (5.0 mL) was degassed under reduced pressure for 30 min. CuI (66.7 mg, 0.35 mmol) was then added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. The suspension was then stirred at 135° C. under nitrogen overnight. The suspension was cooled and diluted with ethyl acetate. The resulting mixture was washed with aqueous LiCl (5%), ammonium hydroxide (2×), and brine. The organic extract was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by preparative TLC (hexanes/ethyl acetate 1:1 then DCM/MeOH 96:4). The desired band was collected and extracted with dichloromethane. The resulting solution was treated with charcoal, filtered through a pad of celite, and concentrated under reduced pressure to give the title compound (36 mg, 20%) as a yellow foam: ¹H NMR (500 MHz, CDCl₃) δ 9.36 (s, 1H), 8.76 (d, J=7.0 Hz, 1H), 8.99 (d, J=6.5 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58-7.56 (m, 1H), 7.38-7.37 (m, 1H), 7.09-7.08 (m, 1H), 6.93 (d, J=7.0 Hz, 1H), 3.80-3.68 (m, 4H), 3.68 (s, 3H), 3.09-2.99 (m, 4H), 1.49 (s, 9H).

d) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one hydrochloride

To a solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (36 mg, 0.067 mmol) in dichloromethane (1.0 mL) was added HCl (2M in diethyl ether, 5.0 mL). The resulting slurry was stirred at room temperature for 14 h and then concentrated under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA). The clean fractions were combined, concentrated under reduced pressure and lypholized overnight. The trifluroacetate salt was dissolved in a 1:2 mixture of acetonitrile and water (10 mL) and passed through a plug of SAX column. The column was further washed with a 1:2 mixture of acetonitrile and water (10 mL). The combined filtrate was lypholized to give the title compound (30.1 mg, 94%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 9.48 (s, 1H), 8.80 (d, J=8.5 Hz, 1H), 8.38 (d, J=6.5 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.0 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.18 (dd, J=8.5, 1.5 Hz, 1H), 3.78 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.50 (t, J=5.5 Hz, 2H), 3.37 (t, J=5.5 Hz, 2H), 3.26 (t, J=5.5 Hz, 2H); ESI MS m/z 440 [M+H]⁺.

Example 59 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(pyridin-2-yl)ethyl)piperazin-2-one dihydrochloride

a) 2-(2-Chloroethyl)pyridine hydrochloride (CAS Registry Number 4226-37-3) (U.S. Pat. No. 2,533,243 to Gump et al., which is hereby incorporated by reference in its entirety)

2-(Pyridin-2-yl)ethanol (7.2 g, 58 mmol) and thionyl chloride (10.6 g, 89.1 mmol) were combined in THF (30 mL) and heated at reflux for 16 h. Upon cooling, the solid was filtered off and washed with THF to provide the title compound (4.2 g, 40%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J=5.6 Hz, 1H), 8.51-8.45 (dt, J=7.8, 1.5 Hz, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.91-7.86 (m, 1H), 4.14 (t, J=6.5 Hz, 2H), 3.53 (t, J=6.5 Hz, 2H).

b) 4-(2-(Pyridin-2-yl)ethyl)piperazin-2-one

Piperazinone (2.2 g, 22 mmol), 2-(2-chloroethyl)pyridine hydrochloride (3.9 g, 22 mmol) and i-Pr₂NEt (5.67 g, 7.6 mL, 44 mmol) were heated at reflux for 16 h. The mixture was concentrated, and the residue was purified by column chromatography (80 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (1.5 g, 33%) as a yellow solid; ESI MS m/z 206 [M+H]⁺.

c) tert-Butyl 6-methyl-8-(2-oxo-4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (200 mg, 0.528 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (118 mg, 0.576 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (52 mg, 20%) as a white solid: ESI MS m/z 504 [M+H]⁻.

d) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(pyridin-2-yl)ethyl)piperazin-2-one dihydrochloride

tert-Butyl 6-methyl-8-(2-oxo-4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (52 mg, 0.10 mmol) was reacted following the procedure for Example 53 (step b) to provide the title compound (23 mg, 49%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.86 (d, J=5.5 Hz, 1H), 8.49-8.46 (dt, J=7.9, 1.5 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.90 (t, J=6.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 4.54 (s, 2H), 4.13 (s, 2H), 4.09 (t, J=5.5 Hz, 2H), 3.80 (t, J=5.0 Hz, 2H), 3.75 (s, 3H), 3.73 (t, J=5.0 Hz, 2H), 3.63-3.56 (m, 4H), 3.20-3.17 (m, 2H), 2.13-2.09 (m, 2H); ESI MS m/z 404 [M+H]⁺; HPLC (Method C) 95.7% (AUC), t_(R)=10.15 min

Example 60 Preparation of 2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one hydrochloride ALB 139968(a)

a) tert-Butyl 6-methyl-8-(6-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-1(6H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.13 g, 0.34 mmol), 5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (0.10 g, 0.67 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (15 mg, 0.10 mmol) and copper iodide (0.16 g, 0.84 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 110° C. for 48 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (30 mL) and washed with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes) gave the title compound (46 mg, 24%) as an orange film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.05 (dd, J=8.5, 1.5 Hz, 1H), 6.56 (d, J=2.5 Hz, 1H), 5.41 (s, 2H), 4.59-4.57 (m, 2H), 3.68-3.64 (m, 5H), 3.01-2.98 (m, 2H), 1.97-1.90 (m, 2H), 1.36-1.27 (m, 9H).

b) 2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one hydrochloride

1.25 M HCl in MeOH (4.0 mL) was added to tert-butyl 6-methyl-8-(6-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-1(6H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (43 mg, 0.075 mmol), and the resulting solution was stirred under N₂ at ambient temperature for 18 h. The solution was concentrated under reduced pressure, and the resulting residue was diluted with MeOH (1.0 mL) and Et₂O (10 mL). The resulting solids were collected by filtration to provide the title compound (23 mg, 61%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (d, J=1.5 Hz, 1H), 8.87 (s, 2H), 8.22 (dd, J=8.5, 1.5 Hz, 1H), 8.02-8.00 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 6.56 (d, J=3.0 Hz, 1H), 5.41 (s, 2H), 4.44 (s, 2H), 3.72 (s, 3H), 3.47-3.43 (m, 2H), 3.10 (t, J=5.5 Hz, 2H), 2.08-2.04 (m, 2H); ESI MS m/z 470 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=14.1 min.

Example 61 Preparation of 1-(2-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5fluoropyridin-2-yl)methyoxy)pyridin-2(1H)-one

Triethylamine (48 μL, 0.34 mmol), DMAP (4.0 mg, 0.034 mmol) and acetyl chloride (18 μL, 0.26 mmol) were added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (78 mg, 0.17 mmol) in CH₂Cl₂ (10 mL), and the resulting solution was stirred at ambient temperature for 3 h under N₂. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 1 column volume, then increased to 0:100 over 10 column volumes and held for 12 column volumes) gave the title compound (55 mg, 70%) as an off-white solid: mp 78-83° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 7.83 (ddd, J=8.5, 8.5, 3.0 Hz, 1H), 7.66-7.49 (m, 3H), 7.39 (dd, J=21.0, 2.0 Hz, 1H), 6.93 (ddd, J=22.5, 8.0, 1.5 Hz, 1H), 6.11 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (dd, J=5.0, 3.0 Hz, 1H), 5.21 (s, 2H), 4.69-4.68 (m, 2H), 3.78-3.75 (m, 2H), 3.67-3.65 (m, 3H), 3.03-2.96 (m, 2H), 2.09-1.90 (m, 5H); ESI MS m/z 461 [M+H]⁺; HPLC (Method A) 98.7% (AUC), t_(R)=16.0 min.

Example 62 Preparation of 1-(2-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one

Triethylamine (58 μL, 0.41 mmol), DMAP (5.0 mg, 0.041 mmol) and acetyl chloride (22 μL, 0.31 mmol) were added to a solution of 1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride (97 mg, 0.21 mmol) in CH₂Cl₂ (15 mL), and the resulting solution was stirred at ambient temperature for 18 h under N₂. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 1 column volume, then increased to 0:100 over 10 column volumes and held for 12 column volumes) gave the title compound (58 mg, 59%) as a yellow powder: mp 156-162° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.72-7.49 (m, 2H), 7.07-6.99 (m, 2H), 6.80-6.78 (m, 1H), 4.72-4.70 (m, 2H), 3.79-3.76 (m, 2H), 3.69-3.68 (m, 3H), 3.05-2.98 (m, 2H), 2.02-1.90 (m, 5H); ESI MS m/z 481 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=18.1 min.

Example 63 Preparation of 4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (300 mg, 0.792 mmol) and 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (187 mg, 0.792 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 30%) as a yellow oil: ESI MS m/z 535 [M+H]⁺.

b) 4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (130 mg, 0.243 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (64 mg, 56%) as a yellow solid: mp 260-266° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.59 (d, J=2.4 Hz, 1H), 7.95-7.91 (dd, J=8.4, 2.4 Hz, 1H), 7.62-7.58 (m, 3H), 7.41 (d, J=1.6 Hz, 1H), 7.05-7.04 (dd, J=8.4, 1.6 Hz, 1H), 6.34-6.30 (dd, J=7.6, 2.7 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 5.26 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.53-3.49 (m, 2H), 3.19-3.17 (m, 2H), 2.19-2.12 (m, 2H); ESI MS m/z 435 [M+H]⁺.; HPLC (Method B)>99% (AUC), t_(R)=12.2 min.

Example 64 Preparation of 4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one hydrochloride

a) tert-Butyl 8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (250 mg, 0.66 mmol) and 4-(4-chlorophenethyl)piperazin-2-one (157 mg, 0.66 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (250 mg, 70%) as a colorless oil: ESI MS m/z 537 [M+H]⁺.

b) 4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one hydrochloride

tert-Butyl 8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (250 mg, 0.465 mmol) was reacted following the procedure for Example 53 (step b) to provide the title compound (116 mg, 53%) as a white solid: mp 252-257° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.91 (s, 2H), 7.57 (d, J=8.7 Hz, 1H), 7.40-7.30 (m, 5H), 6.98 (d, J=8.4 Hz, 1H), 4.42-4.35 (m, 2H), 3.79-3.69 (m, 5H), 3.46-3.36 (m, 2H), 3.26-3.18 (m, 2H), 3.10-3.02 (m, 2H), 2.97-2.76 (m, 4H), 2.72-2.61 (m, 2H), 2.10-1.97 (m, 2H); ESI MS m/z 437 [M+H]⁺; HPLC (Method B) 97.5% (AUC), t_(R)=10.9 min.

Example 65 Preparation of 4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4-(2,4-dichlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (155 mg, 0.411 mmol) and 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (110 mg, 0.411 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (105 mg, 45%) as a yellow foam: ESI MS m/z 568 [M+H]⁺.

b) 4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-(4-(2,4-dichlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (105 mg, 0.184 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (36 mg, 38%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20-9.10 (s, 2H), 7.74 (d, J=2.1 Hz, 1H), 7.68-7.63 (m, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.52-7.51 (dd, J=8.2, 2.0 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.01-6.98 (dd, J=8.4, 1.8 Hz, 1H), 6.12-6.09 (dd, J=7.6, 2.7 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 5.19 (s, 2H), 4.46-4.39 (s, 2H), 3.71 (s, 3H), 3.47-3.30 (m, 2H), 3.14-3.03 (m, 2H), 2.12-1.99 (m, 2H); ESI MS m/z 468 [M+H]⁺; HPLC (Method B) 97.1% (AUC), t_(R)=14.4 min.

Example 66 Preparation of 4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4-(2,4-difluorobenzyloxy)-2-oxopyridin-1 (2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (155 mg, 0.411 mmol) and 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (97 mg, 0.41 mmol) was reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 59%) as a green oil: ESI MS m/z 536 [M+H]⁺.

b) 4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-(4-(2,4-difluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (130 mg, 0.242 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (54 mg, 47%) as a white solid: mp 272-280° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.77 (s, 2H), 7.69-7.63 (m, 2H), 7.55 (d, J=7.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.37-7.32 (dt, J=10.3, 2.5 Hz, 1H), 7.19-7.15 (m, 1H), 7.01-6.99 (dd, J=8.3, 1.8 Hz, 1H), 6.08-6.06 (dd, J=7.5, 2.8 Hz, 1H), 6.04 (d, J=2.8 Hz, 1H), 5.15 (s, 2H), 4.55-4.24 (m, 2H), 3.72 (s, 3H), 3.50-3.41 (m, 2H), 3.10-3.08 (m, 2H), 2.14-1.91 (m, 2H); ESI MS m/z 436 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=13.3 min.

Example 67 Preparation of 4-((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one dihydrochloride

a) tert-Butyl 8-(4-((3,5-dichloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (150 mg, 0.396 mmol) and 4-((3,5-dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one (107 mg, 0.396 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (150 mg, 66%) as a green oil: ESI MS m/z 569 [M+H]⁺.

d) 4-((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one dihydrochloride

tert-Butyl 8-(4-((3,5-dichloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (150 mg, 0.263 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (102 mg, 71%) as a white solid: mp 251-256° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21-8.98 (s, 2H), 8.69 (d, J=2.1 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.01-6.99 (dd, J=8.8, 1.8 Hz, 1H), 6.10-6.09 (dd, J=7.6, 2.8 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 5.30 (s, 2H), 4.43-4.42 (m, 2H), 3.71 (s, 3H), 3.48-3.39 (m, 2H), 3.10-3.07 (m, 2H), 2.14-1.93 (m, 2H); ESI MS m/z 469 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.9 min.

Example 68 Preparation of 4-(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4-(4-chloro-2-fluorobenzyloxy)-2-oxopyridin-1 (2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (150 mg, 0.400 mmol) and 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (101 mg, 0.400 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (107 mg, 48%) as a yellow oil: ESI MS m/z 552 [M+H]⁺.

b) -(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 8-(4-(4-chloro-2-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (107 mg, 0.194 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (59.9 mg, 63%) as a white solid: mp 191-200° C. deliquesce; ¹H NMR (500 MHz, DMSO-d₆) δ 9.22-9.04 (s, 2H), 7.65-7.61 (m, 2H), 7.57-7.53 (m, 2H), 7.48 (d, J=1.8 Hz, 1H), 7.39-7.37 (dd, J=8.1, 1.8 Hz, 1H), 7.00-6.97 (dd, J=8.2, 1.8 Hz, 1H), 6.09-6.07 (dd, J=7.6, 2.8 Hz, 1H), 6.03 (d, J=2.8 Hz, 1H), 5.17 (s, 2H), 4.43-4.41 (m, 2H), 3.71 (s, 3H), 3.38-3.33 (m, 2H), 3.18-3.08 (m, 2H), 2.10-2.06 (m, 2H); ESI MS m/z 452 [M+H]⁺; HPLC (Method B)>96.3% (AUC), t_(R)=14.0 min.

Example 69 Preparation of 1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (34 mg, 0.078 mmol) was reacted following the procedure for Example 29 to provide the title compound (34 mg, 89%) as an orange solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.71 (d, J=8.9 Hz, 1H), 8.47 (d, J=9.1 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.18-7.17 (dd, J=7.2, 2.0 Hz, 1H), 7.15-7.14 (dd, J=8.4, 1.8 Hz, 1H), 4.76 (d, J=14.3 Hz, 1H), 4.54-4.50 (dd, J=14.5, 6.5 Hz, 1H), 3.75 (s, 3H), 3.70-3.64 (m, 1H), 3.46-3.40 (m, 1H), 3.16-3.05 (m, 2H), 2.81 (d, J=5.0 Hz, 3H), 2.20-2.14 (m, 1H), 2.09-2.00 (m, 1H); ESI MS m/z 454 [M+H]⁺; HPLC (Method B) 97% (AUC), t_(R)=12.4 min.

Example 70 Preparation of 1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one hydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one (200 mg, 0.478 mmol) was reacted following the procedure for Example 29 to provide the title compound (201 mg, 90%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.63 (d, J=2.7 Hz, 1H), 7.90-7.88 (dd, J=8.1, 2.8 Hz, 1H), 7.81-7.79 (m, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.51 (d, J=1.7 Hz, 1H), 7.11-7.09 (dd, J=8.4, 1.8 Hz, 1H), 6.57-6.55 (dd, J=7.5, 2.8 Hz, 1H), 6.34 (d, J=2.8 Hz, 1H), 5.39 (s, 2H), 4.80 (d, J=14.8 Hz, 1H), 4.59 (d, J=14.8 Hz, 1H), 3.85-3.75 (m, 4H), 3.56-3.51 (m, 1H), 3.26-3.15 (m, 2H), 2.79 (s, 3H), 2.57-2.31 (m, 1H), 2.19-2.14 (m, 1H); ESI MS m/z 433 [M+H]⁺; HPLC (Method B) 98.8% (AUC), t_(R)=11.7 min.

Example 71 Preparation of 1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride

1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (64 mg, 0.14 mmol) was reacted following the procedure for Example 29 to provide the title compound (30 mg, 42%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.52-10.04 (s, 1H), 8.88 (d, J=1.3 Hz, 1H), 8.20-8.18 (dd, J=8.1, 1.5 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.02-7.00 (dd, J=8.6, 1.8 Hz, 1H), 6.16-6.14 (dd, J=7.6, 2.8 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.35 (s, 2H), 4.72 (d, J=14.2 Hz, 1H), 4.51-4.47 (dd, J=14.6, 6.5 Hz, 1H), 3.72 (s, 3H), 3.70-3.61 (m, 1H), 3.44-3.38 (m, 1H), 3.11-3.04 (m, 2H), 2.79 (d, J=4.9 Hz, 3H), 2.17-2.14 (m, 1H), 2.06-2.03 (m, 1H); ESI MS m/z 483 [M+H]⁺; HPLC (Method B) 98.6% (AUC), t_(R)=13.1 min.

Example 72 Preparation of 1-(2-Cyclobutyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one hydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one (300 mg, 0.717 mmol) was reacted following the procedure for Example 86 to provide the title compound (270 mg, 74%) as a white solid: mp 260-265° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.0-10.35 (s, 1H), 8.61 (d, J=2.9 Hz, 1H), 7.85-7.81 (dt, J=8.8, 2.9 Hz, 1H), 7.66-7.63 (m, 2H), 7.58 (d, J=7.6 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.01-6.99 (dd, J=8.4, 1.9 Hz, 1H), 6.14-6.12 (dd, J=7.6, 1.8 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 5.22 (s, 2H), 4.51 (d, J=14.2 Hz, 1H), 4.14-4.12 (dd, J=14.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.67-3.62 (m, 1H), 3.56-3.52 (m, 1H), 3.30-3.25 (m, 1H), 3.12-3.10 (m, 2H), 2.43-2.39 (m, 1H), 2.29-2.25 (m, 1H), 2.15-2.04 (m, 4H), 1.70-1.68 (m, 1H), 1.62-1.68 (m, 1H); ESI MS m/z 473 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.4 min.

Example 73 Preparation of 1-(2-Ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one hydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one (200 mg, 0.478 mmol) was reacted following the procedure for Example 30 to provide the title compound (23 mg, 10%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.00-9.95 (s, 1H), 8.62 (s, 1H), 7.85-7.80 (dt, J=8.8, 3.0 Hz, 1H), 7.66-7.64 (m, 2H), 7.58 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.14-6.12 (dd, J=7.6, 2.2 Hz, 1H), 5.97 (d, J=2.8 Hz, 1H), 5.21 (s, 2H), 4.72-4.34 (m, 2H), 3.71 (s, 3H), 3.69-3.63 (m, 2H), 3.14-2.68 (m, 4H). 2.16-1.95 (m, 2H), 1.39-1.15 (m, 3H); ESI MS m/z 447 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=12.0 min.

Example 74 Preparation of 1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-one hydrochloride

a) 4-(4-Fluorophenethyl)piperazin-2-one

Piperazinone (1.20 g, 12.1 mmol), 1-fluoro-4-(2-chloroethyl)benzene (2.45 g, 12.1 mmol) and i-Pr₂NEt (3.25 g, 4.5 ml, 25 mmol) were combined in acetonitrile (25 mL) and heated to 85° C. for 2 h. The mixture was concentrated and partitioned between H₂O (20 mL) and CH₂Cl₂ (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH₂Cl₂ (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH₂Cl₂ (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH₂Cl₂ (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.30 g, 48%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.13 (m, 2H), 7.00-6.94 (m, 2H), 6.45 (s, 1H), 3.39-3.35 (m, 2H), 3.20 (s, 2H), 2.78-2.62 (m, 6H).

b) tert-butyl 8-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (514 mg, 1.356 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (301 mg, 1.356 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (537 mg, 76%) as a white solid: ESI MS m/z 521 [M+H]⁺.

c) 4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one

tert-Butyl 8-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (537 mg, mmol) was reacted following the procedure for Example 53 (step b) to provide the title compound (447 mg, >100%) as a yellow foam: ESI MS m/z 421 [M+H]⁺.

d) 1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-one hydrochloride)

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one (100 mg, 0.238 mmol) was reacted following the procedure for Example 29 to provide the title compound (53 mg, 24%) as a white solid: mp 211-220° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.34-7.32 (m, 2H), 7.08-7.04 (m, 3H), 4.75 (d, J=14.1 Hz, 1H), 4.54 (d, J=14.4 Hz, 1H), 4.00-3.85 (m, 2H), 3.80-3.70 (m, 5H), 3.60-3.47 (m, 2H), 3.18-3.15 (m, 5H), 3.03-2.90 (m, 3H), 2.95 (s, 3H), 2.39-2.30 (m, 1H), 2.20-2.15 (m, 1H); ESI MS m/z 435 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=10.4 min.

Example 75 Preparation of 1-(2-Cyclobutyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-one hydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one (100 mg, 0.238 mmol) was reacted following the procedure for Example 86 to provide the title compound (65 mg, 54%) as a white solid: mp 194-205° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.32-7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.61 (d, J=14.6 Hz, 1H), 4.42 (d, J=14.6 Hz, 1H), 3.84-3.79 (m, 3H), 3.75 (s, 3H), 3.69-3.65 (m, 2H), 3.63-3.34 (m, 3H), 3.42-2.78 (m, 7H), 2.51-2.38 (m, 1H), 2.38-2.25 (m, 3H), 2.25-2.03 (m, 2H), 1.87-1.76 (m, 2H); ESI MS m/z 475 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=10.9 min.

Example 76 Preparation of 1-(2-Ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-one hydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one (200 mg, 0.476 mmol) was reacted following the procedure for Example 30 to provide the title compound (105 mg, 46%) as a white solid: mp 190-205° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.61 (d, J=8.4 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.31-7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.72 (d, J=14.9 Hz, 1H), 4.62 (d, J=14.9 Hz, 1H), 3.92-3.79 (m, 2H), 3.86-3.79 (m, 5H), 3.59-3.47 (m, 2H), 3.26-3.17 (m, 6H), 3.00-2.81 (m, 4H), 2.40-2.24 (m, 1H), 2.24-2.00 (m, 1H), 1.38 (t, J=7.3 Hz, 3H); ESI MS m/z 449 [M+H]⁺; HPLC (Method B) 97.3% (AUC), t_(R)=10.6 min.

Example 77 Preparation of 4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)azepane-1-carboxylate

tert-Butyl 4-oxoazepane-1-carboxylate (1.7 g, 8.1 mmol) was added to a solution of 2-bromo-6-hydrazinylpyridine (1.5 g, 8.1 mmol) in Et₂O (27 mL), and the resulting solution was stirred at ambient temperature for 1.5 h. The solution was concentrated under reduced pressure to provide the title compound (3.1 g, 99%) as a light orange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.89-9.68 (m, 1H), 7.50-7.45 (m, 1H), 7.04-7.01 (m, 1H), 6.89-6.85 (m, 1H), 3.48-3.28 (m, 4H), 2.59-2.50 (m, 4H, overlaps with H₂O), 1.69-1.53 (m, 2H), 1.38-1.36 (m, 9H).

b) tert-Butyl 4-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)azepane-1-carboxylate

Sodium hydride (60% dispersion in oil, 0.83 g, 21 mmol) was added to a solution of tert-butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)azepane-1-carboxylate (6.4 g, 17 mmol) in DMF (54 mL) at room temperature under N₂ and stirred for 20 min. Methyl iodide (1.1 mL, 18 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H₂O (100 mL). The solution was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (4×30 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford a dark orange oil. The oil was diluted with EtOAc (100 mL) and washed with brine (6×50 mL), dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure to provide the title compound (7.00 g, quant.) as an amber oil: ¹H NMR (300 MHz, DMSO-d₆) δ 7.44-7.36 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.49-6.38 (m, 1H), 3.56-3.35 (m, 4H), 3.06-3.04 (m, 3H), 2.75-2.50 (m, 4H, overlaps with H₂O), 1.72-1.51 (m, 2H), 1.43-1.15 (m, 9H).

c) tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 4-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)azepane-1-carboxylate (6.66 g, 17.3 mmol) and p-toluene sulfonic acid (6.93 g, 36.4 mmol) were stirred at 175° C. for 55 min. The mixture was cooled to ambient temperature, and the resulting oil was diluted with 1.8:1 H₂O/iPrOH (62 mL). K₂CO₃ (10.5 g, 76.1 mmol) and Boc₂O (4.15 g, 19.3 mmol) were added to the resulting solution and the solution was stirred at ambient temperature for 3 h. The solution was diluted with H₂O (100 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated. Flash chromatography (120 g ISCO column, hexanes/EtOAc, 90:10 for 4 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes, increased to 0:100 over 10 column volumes) provided the title compound (0.85 g, 12%) as a yellow powder: ¹H NMR (300 MHz, DMSO-d₆) δ 7.82 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 3.66-3.64 (m, 5H), 3.55-3.50 (m, 2H, overlap with H₂O), 3.18-3.15 (m, 2H), 3.02-3.00 (m, 2H), 1.41 (s, 9H).

d) tert-Butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.27 g, 0.71 mmol), 4-benzyloxy pyridinone (0.16 g, 0.78 mmol), and Cs₂CO₃ (0.25 g, 0.776 mmol) were suspended in DMSO (4.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (31 mg, 0.21 mmol) and copper iodide (0.17 g, 0.92 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (30 mL) and washed with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes) gave a crude product that was dissolved in CH₂Cl₂ (5 mL). Activated charcoal was added to the solution, and the resulting suspension was filtered through celite. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 75:25 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (0.12 g, 33%) as a clear film: ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.37 (m, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.15 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.69-3.67 (m, 5H), 3.59-3.58 (m, 2H), 3.06-3.05 (m, 2H), 2.96-2.95 (m, 2H), 1.43-1.42 (m, 9H).

e) 4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

1.25 M HCl in MeOH (4 mL) was added to tert-butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.12 g, 0.24 mmol) and the resulting solution was stirred under N₂ at ambient temperature for 18 h. The solution was concentrated to dryness to provide the title compound (0.11 g, quant.) as an orange solid: mp 180-185° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 8.02 (d, J=8.5 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 4H), 7.38 (d, J=7.5 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.16 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.73 (s, 3H), 3.39-3.38 (m, 2H), 3.33-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.14 (t, J=5.5 Hz, 2H); ESI MS m/z 401 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=13.9 min.

Example 78 Preparation of 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.20 g, 0.53 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (0.13 g, 0.55 mmol), and Cs₂CO₃ (0.19 g, 0.58 mmol) were suspended in DMSO (3.0 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (23 mg, 0.16 mmol) and copper iodide (0.13 g, 0.69 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting solution was stirred at ambient temperature for 6 h. The resulting solution was diluted with CH₂Cl₂, the resulting layers were separated, and the aqueous phase was extracted with CH₂Cl₂ (3×25 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (56 mg, 19%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.06-8.03 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 3.72-3.68 (m, 5H), 3.61-3.60 (m, 2H), 3.08-3.07 (m, 2H), 2.99-2.98 (m, 2H), 1.44 (s, 9H).

b) 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride

1.25 M HCl in MeOH (3.2 mL) was added to tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (55 mg, 0.10 mmol), and the resulting solution was stirred under N₂ at ambient temperature for 18 h. The solution was diluted with MeOH (2.2 mL) and Et₂O (25 mL), and the resulting solids were collected by filtration to provide the title compound (37 mg, 76%) as a yellow powder: mp 320-325° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 2H), 9.21 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.5, 2.0 Hz, 1H), 8.10-8.04 (m, 3H), 7.41 (d, J=8.0 Hz, 2H), 7.03 (d, J=1.5 Hz, 1H), 6.85 (dd, J=7.5, 3.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 3.76 (s, 3H), 3.41-3.40 (m, 2H), 3.33-3.31 (m, 2H, overlaps with solvent), 3.17 (t, J=5.5 Hz, 2H); ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 99.0% (AUC), t_(R)=13.6 min.

Example 79 Preparation of 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.13 g, 0.35 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (85 mg, 0.35 mmol), and Cs₂CO₃ (0.13 g, 0.39 mmol) were suspended in DMSO (2.0 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (15 mg, 0.11 mmol) and copper iodide (86 mg, 0.45 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂(30 mL) and washed with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (47 mg, 24%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (d, J=9.0 Hz, 1H), 8.47 (d, J=8.5 Hz, 1H), 8.12 (d, J=7.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.40-7.39 (m, 2H), 7.22 (dd, J=7.0, 2.0 Hz, 1H), 3.73 (s, 3H), 3.71-3.69 (m, 2H), 3.61-3.60 (m, 2H), 3.09-3.08 (m, 2H), 2.99-2.89 (m, 2H), 1.44 (s, 9H).

b) 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride

1.25 M HCl in MeOH (4.3 mL) was added to tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (47 mg, 0.087 mmol), and the resulting solution was stirred under N₂ at ambient temperature for 20 h. The solution was diluted with Et₂O (25 mL), and the resulting solids were collected by filtration to provide the title compound (39 mg, 94%) as a yellow solid: mp 300-305° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 2H), 8.71 (d, J=9.0 Hz, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.23 (dd, J=7.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.46-3.41 (m, 2H), 3.38-3.34 (m, 2H), 3.32-3.30 (m, 2H, overlapped with solvent), 3.17 (t, J=6.0 Hz, 2H); ESI MS m/z 441 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=12.8 min.

Example 80 Preparation of 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 10-methyl-2-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.15 g, 0.40 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (100 mg, 0.42 mmol), and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.13 mmol) and copper iodide (98 mg, 0.51 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 21 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂(30 mL) and washed with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (32 mg, 15%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (dd, J=1.0, 1.0 Hz, 1H), 8.39-8.34 (m, 2H), 8.05-8.03 (m, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.11 (dd, J=7.0, 1.5 Hz, 1H), 3.72 (s, 3H), 3.70 (t, J=5.5 Hz, 2H), 3.61-3.58 (m, 2H), 3.08-3.07 (m, 2H), 2.99-2.98 (m, 2H), 1.44-1.43 (m, 9H).

b) 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one hydrochloride

1.25 M HCl in MeOH (3.0 mL) was added to tert-butyl 10-methyl-2-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (32 mg, 0.060 mmol), and the resulting solution was stirred under N₂ at ambient temperature for 18 h. The solution was concentrated under reduced pressure, the resulting residue was diluted with MeOH (1 mL) and Et₂O (10 mL), and the solids were collected by filtration to provide the title compound (31 mg, quant.) as a yellow powder: mp 310-314° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 9.15 (dd, J=1.0, 1.0 Hz, 1H), 8.41-8.35 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.12 (dd, J=7.0, 2.0 Hz, 1H), 3.76 (s, 3H), 3.42-3.40 (m, 2H), 3.36-3.32 (m, 2H), 3.30-3.28 (m, 2H, overlaps with H₂O), 3.17 (t, J=6.5 Hz, 2H); ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 98.83% (AUC), t_(R)=13.9 min.

Example 81 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.15 g, 0.40 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.42 mmol), and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.13 mmol) and copper iodide (98 mg, 0.51 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 21 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂(30 mL) and washed with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). The resulting organic solution was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the title compound (0.55 mg, 21%) as a clear film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.84-7.79 (m, 2H), 7.67-7.60 (m, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.18 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.69-3.66 (m, 5H), 3.62-3.57 (m, 2H), 3.08-3.04 (m, 2H), 2.99-2.94 (m, 2H), 1.43-1.42 (m, 9H).

b) 4((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

1.25 M HCl in MeOH (6.0 mL) was added to tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.12 g, 0.22 mmol) and the resulting solution was stirred under N₂ at ambient temperature for 20 h. The resulting suspension was diluted with Et₂O (30 mL), and the resulting solids were collected by filtration to provide the title compound (92 mg, 92%) as an off-white solid: mp 238-240° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (s, 2H), 8.62 (d, J=2.0 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.19 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.73 (s, 3H), 3.40-3.37 (m, 2H), 3.34-3.30 (m, 4H), 3.18-3.14 (m, 2H); ESI MS m/z 420 [M+H]⁻; HPLC (Method A) 98.8% (AUC), t_(R)=13.5 min.

Example 82 Preparation of 5-((5-Fluoropyridin-2-yl)methoxy)-2-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridazin-3(2H)-one hydrochloride

a) tert-Butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.18 g, 0.48 mmol), 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (0.11 g, 0.51 mmol), and Cs₂CO₃ (0.20 g, 0.63 mmol) were suspended in DMSO (2.8 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (21 mg, 0.15 mmol) and copper iodide (0.23 mg, 1.2 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 110° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (20 mL), and the resulting solution was stirred at ambient temperature for 6 h. The resulting solution was diluted with CH₂Cl₂, the resulting layers were separated, and the aqueous phase was extracted with CH₂Cl₂ (3×25 mL). Activated charcoal was added to the combined organic extracts, and the resulting suspension was filtered through a silica gel plug. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over 10 column volumes and held for 4 column volumes, then increased to 0:100 over 10 column volumes and held for 4 column volumes) gave the title compound (0.12 mg, 56%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.72-7.67 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.30 (s, 2H), 3.69-3.67 (m, 5H), 3.60-3.57 (m, 2H), 3.08-3.05 (m, 2H), 2.98-2.96 (m, 2H), 1.44-1.42 (m, 9H).

b) 5-((5-Fluoropyridin-2-yl)methoxy)-2-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridazin-3(2H)-one hydrochloride

1.25 M HCl in MeOH (4.0 mL) was added to tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (55 mg, 0.11 mmol), and the resulting solution was stirred under N₂ at ambient temperature for 18 h. Additional 1.25 M HCl in MeOH (2.0 mL) was added, and the resulting solution was stirred at ambient temperature for 24 h. The resulting solution was diluted with Et₂O (30 mL), and the resulting solids were collected by filtration to provide the title compound (35 mg, 73%) as an off-white powder: mp 226-230° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s, 2H), 8.64 (d, J=3.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.85 (ddd, J=11.5, 8.5, 2.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.30 (s, 2H), 3.71 (s, 3H), 3.45-3.39 (m, 2H), 3.38-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.15-3.14 (m, 2H); ESI MS m/z 421 [M+H]⁺; HPLC (Method A) 98.8% (AUC), t_(R)=11.6 min.

Example 83 Preparation of 4-(2,4-Difluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (83 mg, 0.35 mmol), tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (146 mg, 0.384 mmol), CuI (80 mg, 0.42 mmol), 8-hydroxyquinoline (10 mg, 0.070 mmol) and Cs₂CO₃ (125 mg, 0.384 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded a cream colored solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the cream colored solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et₂O (9 mL) was added, the resulting suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 40° C. for 12 h to afford 40 mg (24%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (br s, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.67 (dd, J=15.5, 8.5 Hz, 1H), 7.35 (ddd, J=10.0, 10.0, 2.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.18 (ddd, J=8.5, 8.5, 2.0 Hz, 1H), 6.14 (dd, J=8.0, 3.0 Hz, 1H), 6.06 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.59-3.32 (m, 4H), 3.31-3.26 (m, 2H), 3.17-3.14 (m, 2H); ESI MS m/z 437 [M+H]⁺.

Example 84 Preparation of 4-(4-Chloro-2-fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (75 mg, 0.30 mmol), tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (91 mg, 0.33 mmol), CuI (67 mg, 0.36 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs₂CO₃ (106 mg, 0.326 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄, and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded a cream colored solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the cream colored solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et₂O (4 mL) was added, and the resulting suspension was filtered, the solid was washed with Et₂O and the solid was put in a vacuum oven at 40° C. for 2 d to afford 20 mg (14%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (br s, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz, 1H), 7.54 (dd, J=10.0, 1.5 Hz, 1H), 7.39 (br d, J=8.5 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.15 (dd, J=8.0, 3.0 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 3.74 (s, 3H), 3.60-3.32 (m, 4H), 3.31-3.26 (m, 2H), 3.17-3.12 (m, 2H); ESI MS m/z 453 [M+H]⁺.

Example 85 Preparation of 4-((5-Chloropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (67 mg, 0.28 mmol), tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (129 mg, 0.339 mmol), CuI (64 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg, 0.06 mmol) and Cs₂CO₃ (101 mg, 0.311 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂, and stirred at 135° C. for 16 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure afforded a tan solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the tan solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 15 h. The suspension was filtered, and the solid was washed with Et₂O and freeze dried to afford 51 mg (36%) of the title compound as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (br s, 2H), 8.68 (s, 1H), 8.07-8.00 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.20 (br d, J=6.0 Hz, 1H), 5.97 (br s, 1H), 5.25 (s, 2H), 3.73 (s, 3H), 3.44-3.21 (m, 6H), 3.19-3.11 (m, 2H); ESI MS m/z 436 [M+H]⁺.

Example 86 Preparation of 4-(Benzyloxy)-1-(7-cyclobutyl-10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

2-Picoline borane (43 mg, 0.40 mmol) was added to a solution of 4-(benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride (58 mg, 0.13 mmol) and cyclobutanone (0.10 mL, 1.3 mmol) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at 25° C. for 15 h. Saturated NaHCO₃ solution was added to the reaction solution, and the phases were separated. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. 2 N HCl in Et₂O (0.05 mL, 0.1 mmol) was added to a solution of the white solid in CH₂Cl₂ (5 mL) under N₂, and the resulting solution was stirred at 25° C. for 30 min. The solution was concentrated under reduced pressure and freeze dried to afford 40 mg (63%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 10.65 (br s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.33 (d, J=8.5 Hz, 1H), 6.17 (dd, J=7.5, 2.0 Hz, 1H), 5.99 (d, J=2.0 Hz, 1H), 5.17 (s, 2H), 3.99-3.88 (m, 1H), 3.73 (s, 3H), 3.61-3.52 (m, 2H), 3.41-3.17 (m, 4H), 3.15-3.07 (m, 2H), 2.41-2.25 (m, 4H), 1.83-1.60 (m, 2H); ESI MS m/z 455 [M+H]⁺.

Example 87 Preparation of 4-(Benzyloxy)-1-(7-ethyl-10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

2-Picoline borane (45 mg, 0.42 mmol) was added to a solution of 4-(benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride (62 mg, 0.14 mmol) and acetaldehyde (0.08 mL, 1.4 mmol) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at 25° C. for 2 h. Saturated NaHCO₃ solution was added to the reaction solution, and the phases were separated. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. 2 N HCl in Et₂O (0.05 mL, 0.1 mmol) was added to a solution of the white solid in CH₂Cl₂ (5 mL) under N₂, and the resulting solution was stirred at 25° C. for 30 min. The solution was concentrated under reduced pressure and freeze dried to afford 48 mg (76%) of the title compound as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (br s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.50-7.36 (m, 5H), 7.32 (d, J=8.0 Hz, 1H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.77-3.62 (m, 5H), (m, 8H), 1.32 (t, J=7.0 Hz, 3H); ESI MS m/z 429 [M+H]⁺.

Example 88 Preparation of 4-(Benzyloxy)-1-(7,10-dimethyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

2-Picoline borane (48 mg, 0.45 mmol) was added to a solution of 4-(benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride (66 mg, 0.15 mmol) and formaldehyde (37% weight solution in H₂O, 0.06 mL, 0.8 mmol) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution was added to the reaction solution, and the phases were separated. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. 2 N HCl in Et₂O (0.04 mL, 0.08 mmol) was added to a solution of the white solid in CH₂Cl₂ (5 mL) under N₂, and the resulting solution was stirred at 25° C. for 30 min. The solution was concentrated under reduced pressure and freeze dried to afford 21 mg (31%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 10.35-10.20 (m, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.32 (d, J=8.0 Hz, 1H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.73-3.63 (m, 2H), 3.43-3.22 (m, 5H), 3.12-3.03 (m, 1H), 2.97 (br s, 3H); ESI MS m/z 415 [M+H]⁺.

Example 89 Preparation of 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.15 g, 0.40 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (95 mg, 0.40 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.3 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (91 mg, 0.48 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (40 mL) and washed with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (2×30 mL). The resulting organic solution was dried over Na₂SO₄ and filtered. Activated charcoal was added to the filtrate, the resulting suspension was filtered through a celite plug with 80:18:2 CH₂Cl₂/MeOH/NH₄OH, and the filtrate was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (149 mg, 70%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 1.5 Hz, 1H), 8.07-8.02 (m, 3H), 7.39 (d, J=8.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.84 (dd, 7.5, 2.0 Hz, 1H), 4.61 (s, 2H), 3.74 (s, 3H), 3.68 (t, J=5.5 Hz, 2H), 3.05 (t, J=5.5 Hz, 2H), 1.98-1.93 (m, 2H), 1.36-1.28 (m, 9H).

b) 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride

A suspension of tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-d]azepine-6(5H)-carboxylate (149 mg, 0.276 mmol) in 1.25 M HCl in MeOH (3.0 mL) was stirred under N₂ at ambient temperature for 18 h. CH₂Cl₂ (1.5 mL) was added to the suspension and the resulting solution was stirred at ambient temperature for 18 h. CH₂Cl₂ (1.0 mL) and 1.25 M HCl in MeOH (1.0 mL) were added to the solution, and the resulting solution was stirred at ambient temperature for 6 h. Additional 1.25 M HCl in MeOH (2.0 mL) was added to the solution, and the resulting solution was stirred for 18 h. The solution was diluted with Et₂O, and the resulting solids were collected by filtration to afford the title compound (104 mg, 79%) as a light-yellow powder: mp 308-312° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (d, J=2.0 Hz, 1H), 9.04 (s, 2H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.85 (dd, J=7.5, 2.0 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.49-3.46 (m, 2H), 3.17-3.15 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 98.1% (AUC), t_(R)=13.4 min.

Example 90 Preparation of 4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) 2-Bromo-6-hydrazinylpyridine (CAS Registry Number 26944-71-8) (Yakhontov et al., Khimiya Geterotsiklicheskikh Soedinenii 6:1121-1126 (1969), which is hereby incorporated by reference in its entirety)

Hydrazine (27 mL, 83 mmol) was added to 2,6-dibromopyridine (20 g, 84 mmol), and the resulting suspension was heated at 70° C. for 30 min. The solution was cooled to 50° C. and diluted with H₂O (150 mL). The resulting solids were stirred for 2 h. The solids were collected by filtration and washed with H₂O (350 mL) to afford the title compound (13 g, 83%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 6.66 (t, J=7.8 Hz, 2H), 4.19 (s, 2H).

b) 2-Bromo-6-(2-cyclohexylidenehydrazinyl)pyridine (CAS Registry Number 20798-52-1) (Yakhontov et al., Zhurnal Organicheskoi Khimii 4:1675-1678 (1968), which is hereby incorporated by reference in its entirety)

Cyclohexanone (2.8 mL, 27 mmol) was added to a solution of 2-bromo-6-hydrazinylpyridine (5.1 g, 27 mmol) in Et₂O (92 mL), and the resulting solution was stirred at ambient temperature for 1 h. The solution was concentrated under reduced pressure to provide the title compound (7.3 g, quant.) as an off-white foam: ¹H NMR (500 MHz, DMSO-d₆) δ 9.86 (s, 1H), 7.46 (dd, J=8.0, 8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.83 (dd, J=7.5, 0.5 Hz, 1H), 2.45 (s, 2H), 2.25 (t, J=6.0 Hz, 2H), 1.62-1.61 (m, 2H), 1.56-1.55 (m, 4H).

c) 2-Bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b] indole (CAS Registry Number 20798-17-8) (Yakhontov et al., Zhurnal Organicheskoi Khimii 4:1675-1678 (1968), which is hereby incorporated by reference in its entirety)

Following a procedure similar to that of Yakhontov and Pronina (Zhurnal Organicheskoi Khimii 1968, 4, 1675-1678), 2-bromo-6-(2-cyclohexylidenehydrazinyl)pyridine (9.9 g, 37 mmol) and p-toluene sulfonic acid (15 g, 77 mmol) were heated at 160° C. for 25 min. The resulting solution was cooled to ambient temperature and diluted with H₂O (100 mL) and saturated NaHCO₃ solution (50 mL). EtOAc (100 mL) was added, and the resulting solids were collected by filtration. The filtrate was extracted with EtOAc (3×50 mL), and the combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was stirred in EtOAc (50 mL), and the resulting solids were removed by filtration to provide additional crude title compound. The solids were combined and washed with 5:1 MeOH/CH₂Cl₂ and EtOAc sequentially to provide the title compound (3.4 g, 37%) as a tan solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.42 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 2.68 (t, J=6.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 1.84-1.76 (m, 4H).

d) 2-Bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one

A solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (3.84 g, 15.2 mmol) in THF (135 mL) and H₂O (15.2 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.92 g, 30.5 mmol) in THF (60.3 mL) at such a rate that the reaction mixture did not exceed 0° C. The resulting solution was warmed to ambient temperature and stirred for 5 h. The solution was diluted with saturated NaHCO₃ solution (100 mL), and the aqueous solution was extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Flash chromatography (80 g ISCO dry load 80:18:2 CH₂Cl₂/MeOH/NH₄OH, 1000 mL) followed by trituration with MeOH provided the title compound (1.58 g, 39%) as an off-white solid: ¹H NMR (500 MHz, THF-d₈) δ 8.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0, 1H), 4.73 (s, 1H), 3.02 (t, J=8.0 Hz, 2H), 2.51-2.47 (m, 2H), 2.27-2.22 (m, 2H); ESI MS m/z 265 [M+H]⁺.

e) 2-Bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one

Methyl iodide (0.45 mL, 7.1 mmol) was added to a solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.6 g, 5.9 mmol) and Cs₂CO₃ (2.3 g, mmol) in DMF (21 mL) under N₂ and stirred for 3 h at ambient temperature. The mixture was quenched with H₂O (30 mL), upon which a solid precipitated out of solution. The solids were collected by filtration and washed with H₂O (100 mL) to provide the title compound (1.47 g, 88%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 3.74 (s, 3H), 3.03 (t, J=6.0 Hz, 2H), 2.50-2.44 (m, 2H, overlap with H₂O peak), 2.20-2.12 (m, 2H).

f) 2-Bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one oxime

Hydroxylamine hydrochloride (0.54 g, 7.9 mmol) and sodium acetate (0.65 g, 7.9 mmol) were added to a suspension of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.5 g, 5.3 mmol) in EtOH (13 mL) and H₂O (5 mL), and the resulting suspension was heated at reflux for 4 h. The reaction was cooled to ambient temperature, and the solids were collected by filtration. The solids were washed with EtOH to provide the title compound (1.34 g, 87%) as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.68 (s, 3H), 2.86 (t, J=6.0 Hz, 2H), 2.68 (t, J=8.0 Hz, 2H), 1.96-1.84 (m, 2H).

g) 2-Bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-5(6H)-one

A suspension of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one oxime (1.3 g, 4.5 mmol) in PPA (20 g) was mechanically rotated in a water bath set at 100° C. for 8 h. The reaction mixture was cooled in an ice bath and quenched with H₂O. 6 N NaOH solution was added until ˜pH 7 and solids precipitated out of solution. The solids were collected by filtration and washed with H₂O to provide the title compound (1.2 g, 89%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (d, J=8.0 Hz, 1H), 7.69 (t, J=5.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H) 3.69 (s, 3H), 3.23-3.20 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), 2.07-2.05 (m, 2H).

h) tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

BH₃.THF (1.0 M solution in THF, 23 mL, 23 mmol) was slowly added to a solution of 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-5(6H)-one (0.50 g, 1.7 mmol) in THF (28 mL), and the resulting solution was heated at reflux for 18 h. The reaction was cooled, and 12 N HCl (˜6 mL) was added slowly. The solution was diluted with H₂O (60 mL) and heated at reflux for 4 h. The solution was cooled to ambient temperature and made basic by the slow addition of aqueous 6 N NaOH. The solution was extracted with EtOAc (100 mL) and CH₂Cl₂ (2×50 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure to provide a yellow film. DMAP (23 mg, catalytic) and Boc₂O (0.48 g, 2.2 mmol) were added to a solution of the yellow film in CH₂Cl₂ (7 mL) under N₂, and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with H₂O and extracted with CH₂Cl₂ (3×25 mL). The combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO column, hexanes/EtOAc, 90:10 for 4 column volumes, increased to 50:50 over 12 column volumes and held for 2 column volumes; increased to 0:100 over 10 column volumes) provided the title compound (0.52 g, 81%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 4.55-4.51 (m, 2H), 3.68 (s, 3H), 3.64 (t, J=5.0 Hz, 2H), 2.98 (t, J=5.5 Hz, 2H), 1.94-1.90 (m, 2H), 1.35-1.22 (m, 9H).

i) tert-Butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

A suspension of tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.15 g, 0.40 mmol), 4-benzyloxypyridinone (80 mg, 0.40 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) in DMSO (2.3 mL) was placed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (91 mg, 0.48 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (40 mL) and washed with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (2×30 mL). The resulting organic solution was dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (141 mg, 70%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.98-7.95 (m, 1H), 7.81-7.79 (m, 1H), 7.49-7.37 (m, 5H), 7.30-7.27 (m, 1H), 6.15 (dd, J=7.8, 2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.58 (br s, 2H), 3.71 (s, 3H), 3.66 (t, J=5.4 Hz, 2H), 3.03-3.01 (m, 2H), 1.98-1.93 (m, 2H), 1.35-1.27 (m, 9H); ESI MS m/z 501 [M+H]⁺.

j) 4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A solution of tert-butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (140 mg, 0.028 mmol) in 1.25 M HCl in MeOH (6.0 mL) was stirred under N₂ at ambient temperature for 18 h. Additional 1.25 M HCl in MeOH was added, and the solution was stirred at ambient temperature for 18 h. The solution was concentrated to dryness to yield the title compound (130 mg, quant.) as a light-yellow powder: mp 328-332° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.34 (m, 2H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.44-3.43 (m, 2H), 3.14-3.12 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 401 [M+H]⁺; HPLC (Method A)>99% (AUC), t_(R)=13.3 min.

Example 91 Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.21 g, 0.56 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.12 g, 0.56 mmol), and Cs₂CO₃ (0.12 g, 0.61 mmol) were suspended in DMSO (3.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol) and copper iodide (0.13 g, 0.67 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N₂. The mixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH₂Cl₂ (40 mL) and washed with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (2×30 mL). The resulting organic solution was dried over Na₂SO₄ and filtered. Activated charcoal was added to the filtrate; the resulting suspension was filtered through a celite plug with 80:18:2 CH₂Cl₂/MeOH/NH₄OH; and the filtrate was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (130 mg, 45%) as an off-white foam: ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (dd, J=7.5, 7.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.28 (dd, J=8.5, 8.5 Hz, 1H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 4.58 (s, 2H), 3.71 (s, 3H), 3.66 (t, J=5.0 Hz, 2H), 3.03 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H), 1.35-1.27 (m, 9H).

b) 4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (130 mg, 0.250 mmol) in 1.25 M HCl in MeOH (4.0 mL) was stirred at ambient temperature for 72 h. The solution was concentrated and dried to provide the title compound (108 mg, 95%) as a brown-yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 2H), 8.62 (d, J=3.0 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 7.88-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.19 (dd, J=8.0, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.49-3.40 (m, 2H), 3.36-3.20 (m, 2H), 2.19-2.08 (m, 2H); ESI MS m/z 420 [M+H]⁺; HPLC (Method A) 98.2% (AUC), t_(R)=12.2 min.

Example 92 Preparation of 1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(5-(trifluoromethyl)pyridine-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (72 mg, 0.30 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (125 mg, 0.329 mmol), CuI (64 mg, 0.34 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs₂CO₃ (107 mg, 0.329 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a yellow foam. 1.25 N HCl in MeOH (5 mL) was added to the yellow foam under N₂, and the resulting suspension was stirred at 25° C. for 20 h. The suspension was concentrated; the residue was diluted with MeOH (5 mL); and the suspension was sonicated for 5 min. Et₂O (50 mL) was added, and the suspension was filtered to afford 33 mg (23%) of the title compound as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.89 (br s, 2H), 8.43-8.35 (m, 2H), 8.23 (d, J=8.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.31 (d, J=1.5, 1H), 7.13 (dd, J=8.0, 2.0 Hz, 1H), 4.53-4.48 (m, 2H), 3.80 (s, 3H), 3.51-3.45 (m, 2H), 3.19-3.15 (m, 2H), 2.12-2.08 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 93 Preparation of 4-(2,4-Dichlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (85 mg, 0.31 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (131 mg, 0.345 mmol), CuI (71 mg, 0.38 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs₂CO₃ (112 mg, 0.345 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH), 100:0 to 0:100) afforded a tan solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the tan solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 24 h. The suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 45° C. for 1 h to afford 102 mg (64%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.88-8.81 (m, 2H), 8.16 (d, J=8.5 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.53 (dd, J=8.0, 2.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0, 2.5 Hz, 1H), 6.03 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 4.52-4.48 (m, 2H), 3.77 (s, 3H), 3.50-3.43 (m, 2H), 3.19-3.12 (m, 2H), 2.13-2.05 (m, 2H); ESI MS m/z 469 [M+H]⁻

Example 94 Preparation of 4-(2,4-Difluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (68 mg, 0.29 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (120 mg, 0.316 mmol), CuI (65 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg, 0.06 mmol) and Cs₂CO₃ (103 mg, 0.316 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded a tan residue. 2 N HCl in Et₂O (100 mL) was added to a solution of the tan residue in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 40° C. for 1 h to afford 47 mg (35%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (br s, 2H), 8.16 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.67 (dd, J=15.5, 8.5 Hz, 1H), 7.40-7.34 (m, 2H), 7.18 (ddd, J=8.5, 8.5, 2.5 Hz, 1H), 7.15 (dd, J=8.0, 3.0 Hz, 1H), 6.06 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.51-4.45 (m, 2H), 3.77 (s, 3H), 3.60-3.42 (m, 2H), 3.17-3.13 (m, 2H), 2.12-2.05 (m, 2H); ESI MS m/z 437 [M+H]⁺.

Example 95 Preparation of 1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (79 mg, 0.33 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (114 mg, 0.300 mmol), CuI (68 mg, 0.36 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs₂CO₃ (108 mg, 0.33 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded a yellow solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) afforded a yellow residue. 2 N HCl in Et₂O (100 mL) was added to a solution of the yellow residue in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 18 h. The suspension was filtered, and the solid was washed with Et₂O and put in a vacuum oven at 50° C. for 1.5 h to afford 45 mg (34%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (br s, 2H), 8.22 (d, J=8.0 Hz, 1H), 8.05-8.00 (m, 3H), 7.89 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0, 1H), 6.90 (s, 1H), 6.79 (d, J=8.5 Hz, 1H), 4.53-4.47 (m, 2H), 3.79 (s, 3H), 3.52-3.25 (m, 2H), 3.20-3.13 (m, 2H), 2.13-2.07 (m, 2H); ESI MS m/z 439 [M+H]⁺.

Example 96 Preparation of 4-(4-Chloro-2-fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (46 mg, 0.18 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (76 mg, 0.20 mmol), CuI (41 mg, 0.22 mmol), 8-hydroxyquinoline (5 mg, 0.04 mmol) and Cs₂CO₃ (65 mg, 0.20 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N₂ and stirred at 135° C. for 21 h. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded a clear solid. 2 N HCl in Et₂O (100 mL) was added to a solution of the clear solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension was stirred at 25° C. for 22 h. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et₂O was added, and the resulting suspension was filtered. The solid was washed with Et₂O and put in a vacuum oven at 40° C. for 1 h to afford 39 mg (44%) of the title compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (br s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz, 1H), 7.55 (dd, J=10.0, 2.0 Hz, 1H), 7.41-7.35 (m, 2H), 6.15 (dd, J=8.0, 2.5 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 4.52-4.45 (m, 2H), 3.76 (s, 3H), 3.60-3.31 (m, 2H), 3.17-3.11 (m, 2H), 2.13-2.04 (m, 2H); ESI MS m/z 453 [M+H]⁺.

Example 97 Preparation of 4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-one dihydrochloride

a) tert-Butyl 8-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (230 mg, 0.609 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (123 mg, 0.534 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (199 mg, 71%) as a colorless oil: ESI MS m/z 521 [M+H]⁺.

b) 4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-one dihydrochloride

tert-Butyl 8-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (199 mg, 0.382 mmol) was reacted following the procedure for Example 53 (step b) to provide the title compound (152 mg, 81%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.96 (s, 1H), 9.40-9.23 (m, 2H), 7.50 (d, J=8.3 Hz, 1H), 7.38-7.35 (m, 3H), 7.20 (t, J=8.6 Hz, 2H), 6.97 (d, J=8.2 Hz, 1H), 4.23-3.79 (br m, 5H), 3.79-3.42 (br m, 8H), 3.40-3.34 (m, 2H), 3.29-3.22 (m, 2H), 3.19-3.04 (m, 4H); ESI MS m/z 421 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=10.5 min.

Example 98 Preparation of 1-(3,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-one dihydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-one dihydrochloride (50 mg, 0.10 mmol) was reacted following the procedure for Example 29 to provide the title compound (33 mg, 66%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.46 (s, 1H), 10.50 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.40-7.33 (m, 3H), 7.25-7.14 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 4.21-3.79 (m, 5H), 3.75-3.39 (m, 7H), 3.38-3.17 (m, 6H), 3.17-3.01 (m, 3H), 2.94 (d, J=4.9 Hz, 3H); ESI MS m/z 435 [M+H]⁺; HPLC (Method B) 98.4% (AUC), t_(R)=10.2 min.

Example 99 Preparation of 1-(3-Ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-one dihydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-one dihydrochloride (50 mg, 0.10 mmol) was reacted following the procedure for Example 30 to provide the title compound (31 mg, 63%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.44 (s, 1H), 10.16 (s, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.41-7.38 (m, 3H), 7.23-7.15 (m, 2H), 6.97 (d, J=8.2 Hz, 1H), 4.23-3.79 (m, 5H), 3.71-3.43 (m, 6H), 3.38-3.17 (m, 9H), 3.17-3.01 (m, 3H), 1.31 (t, J=7.2 Hz, 3H); ESI MS m/z 449 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=10.5 min.

Example 100 Preparation of 4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 2-Chloro-4-(4-chlorobenzyloxy)pyridine

A mixture of 2-chloro-4-iodopyridine (5.0 g, 21 mmol), 4-chlorobenzyl alcohol (3.3 g, 23 mmol), cesium carbonate (8.9 g, 27 mmol), CuI (4.0 g, 21 mmol) and phenanthronine (0.76 g, 4.2 mmol) in toluene (20.0 mL) was purged with nitrogen for 10 min. The reaction mixture was heated at 105° C. overnight and then cooled and diluted with EtOAc. The resulting solution was washed with brine, passed through a pad of celite and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (hexanes/EtOAc 100% to 70%) to give the title compound (3.0 g, 56%): ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=6.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 6.90 (d, J=2.0 Hz, 1H), 6.80 (dd, J=6.0, 2.0 Hz, 1H), 4.07 (s, 2H).

b) 4-(4-Chlorobenzyloxy)pyridin-2(1)-one (CAS Registry Number 191090-84-3) (Wu et al., Tetrahedron Letters 38:3135-3138 (1997), which is hereby incorporated by reference in its entirety)

A mixture of 2-chloro-4-(4-chlorobenzyloxy)pyridine (3.1 g, 12 mmol) and ammonium acetate (4.7 g, 61 mmol) in formic acid (20 mL, 90% in water) and water (20 mL) was heated under reflux for 4 days and then concentrated under reduced pressure. The residue was dissolved in DCM, basified with aqueous sodium bicarbonate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was triturated with DCM to give the title compound (1.1 g, 39%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 12.27-12.10 (br s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 1H), 6.03 (dd, J=6.5, 2.0 H, 1H), 5.92 (d, J=2.0 Hz, 1H), 4.99 (s, 2H).

c) 4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

A suspension of 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (91.0 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H) carboxylate (160 mg, 0.42 mmol), 8-hydroxyquinoline (11 mg, 0.072 mmol) and Cs₂CO₃ (137 mg, 0.42 mmol) in DMSO (10.0 mL) was degassed under reduced pressure for 40 min. CuI (87 mg, 0.46 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 2×5 min. The reaction mixture was heated at 135° C. under nitrogen overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine. The resulting solution was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1.0 mL), and HCl (2M in diethyl ether, 5.0 mL) was added. The resulting slurry was stirred at room temperature overnight and concentrated under reduced pressure. Purification by preparative HPLC followed by preparative TLC (DCM/MeOH/concentrated ammonia 96:3.6:0.4) and preparative HPCL afforded the title compound (41 mg, 23%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.39 (d, J=1.5 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.28 (dd, J=8.0, 3.0 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.54 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.35-3.33 (m, 2H), 3.23 (t, J=5.5 Hz, 2H); ESI MS m/z 434 [M+H]⁺.

Example 101 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-phenethylpyrimidin-2(1H)-one hydrochloride

a) (E)-2-Methoxy-4-styrylpyrimidine

A solution of 4-chloro-2-methoxypyrimidine (0.36 g, 2.5 mmol), trans-2-phenylvinylboronic acid (0.56 g, 3.8 mmol) and potassium carbonate (0.69 g, 5.0 mmol) in DMSO (8.0 mL) was purged with argon for 5 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.18 g, 0.25 mmol) was added to the above solution. The reaction mixture was purged with argon for 5 min and then heated at 95° C. for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water (2×) and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel hexanes/ethyl acetate 95:5 to 60:40) to afford the title compound (0.51 g, 96%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.47 (d, J=5.0 Hz, 1H), 7.92 (d, J=16.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.42-7.35 (m, 3H), 7.01 (d, J=16.0 Hz, 1H), 6.94 (d, J=5.0 Hz, 1H), 4.07 (s, 3H).

b) 2-Methoxy-4-phenethylpyrimidine

To a solution of (E)-2-methoxy-4-styrylpyrimidine (0.51 g, 2.4 mmol) in methanol (25 mL) was added palladium on carbon (0.18 g). The reaction mixture was stirred under hydrogen balloon for 3 days and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to provide the title compound (0.50 g, 97%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.35 (d, J=5.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.21-7.18 (m, 3H), 6.72 (d, J=5.0 Hz, 1H), 4.02 (s, 3H), 3.08-2.98 (m, 4H).

c) 4-Phenethylpyrimidin-2(1H)-one

A solution of 2-methoxy-4-phenethylpyrimidine (0.50 g, 2.3 mmol) in concentrated HCl (4.0 mL) was heated under reflux for 16 h. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with water and dried under reduced pressure to give the title compound (0.34 g, 74%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.52 (d, J=6.5 Hz, 1H), 7.33-7.24 (m, 5H), 6.78 (d, J=6.0 Hz, 1H), 3.12-3.07 (m, 4H).

d) tert-Butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3 (6H) carboxylate

A suspension of 4-phenethylpyrimidin-2(1H)-one (55 mg, 0.28 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-]indole-3(6H) carboxylate (0.13 g, 0.34 mmol), 8-hydroxyquinoline (10 mg, 0.07 mmol) and Cs₂CO₃ (0.12 g, 0.36 mmol) in DMSO (4.5 mL) was degassed under reduced pressure for 15 min. CuI (65 mg, 0.34 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. The suspension was heated at 135° C. in a microwave for 150 min, and then the mixture was cooled and diluted with ethyl acetate. The resulting mixture was washed with aqueous LiCl (5%), ammonium hydroxide (2×) and brine. The organic extract was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was dissolved in DCM, treated with charcoal for 20 min and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (DCM to DCM/MeOH 95:5) to give the title compound (45 mg, 32%) as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.65 (d, J=6.5 Hz, 1H), 7.52 (t, J=8.5 Hz, 1H), 7.33-7.26 (m, 5H), 7.24 (t, J=7.0 Hz, 1H), 7.01 (t, J=8.5 Hz, 1H), 6.22 (d, J=7.0 Hz, 1H), 3.81-3.65 (m, 4H), 3.65 (s, 3H), 3.15-3.12 (m, 2H), 3.07-2.98 (m, 6H), 1.50-1.48 (m, 9H).

e) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-phenethylpyrimidin-2(1H)-one hydrochloride

To a solution of tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H) carboxylate (44 mg, 0.088 mmol) in dichloromethane (4.0 mL) was added HCl (2M in diethyl ether, 4.0 mL). The resulting slurry was stirred at room temperature for 2 days and then concentrated under reduced pressure. The residue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA). The clean fractions were combined and concentrated under reduced pressure. The resulting trifluoroacetate salt was treated with aqueous sodium carbonate and extracted with EtOAc (2×). The combined organic extract was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The free base was converted to the HCl salt using HCl in methanol and lypholized to provide the title compound (19.8 mg, 52%) as a light yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.03 (d, J=7.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.30-7.28 (m, 4H), 7.22-7.17 (m, 1H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 6.56 (d, J=6.5 Hz, 1H), 3.73 (s, 3H), 3.42-3.34 (m, 4H), 3.27-3.25 (m, 2H), 3.17-3.15 (m, 2H), 3.10-3.08 (m, 2H), 3.04-3.02 (m, 2H); ESI MS m/z 399 [M+H]⁺.

Example 102 Preparation of 4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) 2((2-Chloropyridin-4-yloxy)methyl)-3,5-difluoropyridine

(3,5-Difluoropyridin-2-yl)methanol (4.15 g, 28.4 mmol), 2-chloro-4-iodopyridine (7.47 g, 31.2 mmol), cesium carbonate (12.0 g, 36.3 mmol), CuI (5.40 g, 28.4 mmol) and 1,10-phenanthroline (1.02 g, 5.60 mmol) were stirred in toluene (20 mL) and purged with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 60% ethyl acetate) to yield the title compound (3.42 g, 47%) as a yellow oil; ESI MS m/z 257 [M+H]⁺.

b) 4((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one

2((2-Chloropyridin-4-yloxy)methyl)-3,5-difluoropyridine (3.42 g, 13.3 mmol) and ammonium acetate (20.5 g, 267 mmol) were heated at 110° C. in formic acid (45 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO₃ solution. The solid was filtered off to provide the title compound (2.02 g, 63%) as a white solid; ESI MS m/z 239 [M+H]⁺.

c) tert-Butyl 8-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H) carboxylate

4((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.418 mmol) and tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (206 mg, 0.544 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (70 mg, 30%) as a brown oil; ESI MS m/z 537 [M+H]⁺.

d) 4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2 (1H)-one hydrochloride

tert-Butyl 8-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H) carboxylate (70 mg, 0.127 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (36 mg, 60%) as an orange solid: mp 215-225° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 2H), 8.60 (d, J=2.3 Hz, 1H), 8.08-8.06 (m, 1H), 7.56-7.53 (m, 2H), 7.43 (d, J=1.7 Hz, 1H), 6.95-6.94 (dd, J=8.4, 1.8 Hz, 1H), 6.09-6.05 (m, 2H), 5.27 (d, J=1.6 Hz, 2H), 3.69 (s, 3H), 3.37-3.35 (m, 2H), 3.35-3.32 (m, 2H), 3.26-3.24 (m, 2H), 3.13-3.11 (m, 2H); ESI MS m/z 437 [M+H]⁺; HPLC (Method B) 96.5% (AUC), t_(R)=13.1 min.

Example 103 Preparation of 4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1 (2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2 (1H)-carboxylate

A suspension of 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (95 mg, 0.43 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (180 mg, 0.47 mmol), 8-hydroxyquinoline (13 mg, 0.086 mmol) and Cs₂CO₃ (154 mg, 0.47 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (98 mg, 0.52 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 2×5 min. The reaction mixture was then heated at 135° C. under nitrogen overnight. The reaction suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was dissolved in DCM and stirred with charcoal for 10 min. The suspension was filtered, concentrated and purified to afford the title compound (0.12 g, 54%) as a mixture of rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J=8.5 Hz, 0.4H), 7.53 (d, J=8.0 Hz, 0.6H), 7.41 (dd, J=8.0, 6.0 Hz, 2H), 7.33-7.26 (m, 2H), 7.10 (t, J=8.5 Hz 2H), 7.00 (d, J=8.0 Hz, 1H), 6.07 (s, 1H), 6.02 (d, J=5.5 Hz, 1H), 5.01 (s, 2H), 4.71 (s, 0.7H), 4.63 (s, 1.3H), 3.76 (br s, 1.3H), 3.68 (br s, 0.7H), 3.65 (s, 3H), 2.97 (br s, 2H), 2.05-2.03 (m, 2H), 1.44 (s, 3.1H), 1.37 (s, 5.9H).

b) 4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

To a solution of tert-butyl 8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (120 mg, 0.23 mmol) in dichloromethane (1.0 mL) was added HCl (2M in diethyl ether, 5.0 mL). The resulting slurry was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA). The clean fractions were combined and concentrated under reduced pressure. The trifluoracetate salt was converted to HCl salt by dissolving in 1.25 M HCl in methanol and concentrating the resulting solution to dryness. This process was repeated three times to afford the title compound (40.0 mg, 38%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.51 (dd, J=8.5, 5.5 Hz, 2H), 7.44 (s, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.06 (dd, J=8.5, 2.0 Hz, 1H), 6.28 (dd, J=7.5, 3.0 Hz, 1H), 6.12 (d, J=3.0 Hz, 1H), 5.16 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.58 (t, J=5.5 Hz, 2H), 3.20 (t, J=5.5 Hz, 2H), 2.23-2.19 (m, 2H); ESI MS m/z 418 [M+H]⁺.

Example 104 Preparation of 8-(4-((5-Fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (100 mg, 0.340 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (102 mg, 0.510 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (32 mg, 21%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, J=8.6 Hz, 1H), 8.48 (s, 1H), 7.51-7.46 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.17 (dd, J=8.5, 1.8 Hz, 1H), 6.12-6.03 (m, 2H), 5.93-5.86 (m, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 3.42-3.34 (m, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.28-2.19 (m, 2H); ESI MS m/z 433 [M+H]⁺; HPLC (Method B) 98.7% (AUC), t_(R)=13.8 min.

Example 105 Preparation of 4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4-(4-chlorobenzyloxy)-2-oxopyridin-1 (2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2 (1H)-carboxylate

A suspension of 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (84 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (160 mg, 0.42 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and Cs₂CO₃ (137 mg, 0.42 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (87.0 mg, 0.42 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 10 min. The reaction mixture was heated at 135° C. under nitrogen overnight. The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the resulting suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was dissolved in DCM and stirred with charcoal for 10 min. The suspension was filtered, concentrated and purified by prep-TLC (CH₂Cl₂/MeOH 95:5) to afford the title compound (0.10 g, 49%) as a light yellow solid and as a mixture of rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J=7.0 Hz, 0.3H), 7.53 (d, J=8.0 Hz, 0.7H), 7.39 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.35-7.27 (m, 2H), 6.99 (d, J=8.5 Hz, 1H), 6.05 (s, 1H), 6.03 (dd, J=7.5, 2.0 Hz, 1H), 5.02 (s, 2H), 4.71 (s, 0.7H), 4.63 (s, 1.3H), 3.76-3.65 (m, 2H), 3.65 (s, 3H), 2.99-2.97 (m, 2H), 2.05-2.00 (m, 2H), 1.44 (s, 3.3H), 1.37 (s, 5.7H).

b) 4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

To a solution of tert-butyl 8-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (100 mg, 0.19 mmol) in dichloromethane (20 mL) was trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA). The clean fractions were combined and concentrated under reduced pressure. The trifluoracetate salt was converted to the HCl salt by dissolving in 1.25 M HCl in methanol and concentrating the resulting solution to dryness. This process was repeated three times afforded the title compound (35 mg, 39%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.64 (d, J=8.0 Hz, 2H), 7.48-7.42 (m, 5H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 6.37 (dd, J=7.5, 2.5 Hz, 1H), 6.17 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.59-3.57 (m, 2H), 3.22-3.19 (m, 2H), 2.26-2.18 (m, 2H); ESI MS m/z 434 [M+H]⁺.

Example 106 Preparation of 4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 8-(4((3, 5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1 (2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

4-((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (206 mg, 0.544 mmol) and tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (100 mg, 0.418 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (117 mg, 50%) as a yellow oil; ESI MS m/z 537 [M+H]⁺;

b) 4-((3, 5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-d]indol-8-yl)pyridin-2 (1H)-one hydrochloride

tert-Butyl 8-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (111 mg, 0.208 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (87 mg, 89%) as a pink solid: mp 180-190° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (s, 2H), 8.60 (d, J=2.3 Hz, 1H), 8.10-8.06 (dt, J=10.2, 2.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 7.01-6.99 (dd, J=10.0, 2.6 Hz, 1H), 6.09-6.06 (m, 2H), 5.26 (s, 2H), 4.42-4.40 (m, 2H), 3.71 (s, 3H), 3.44-3.41 (m, 2H), 3.10-3.08 (m, 2H), 2.09-2.03 (m, 2H); ESI MS m/z 437 [M+H]⁺; HPLC (Method B) 96.5% (AUC), t_(R)=13.6 min.

Example 107 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-phenethylpyrimidin-2(1H)-one hydrochloride

a) tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1 (2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2 (1H) carboxylate

A suspension of 4-phenethylpyrimidin-2(1H)-one (55 mg, 0.28 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (0.13 g, 0.34 mmol), 8-hydroxyquinoline (10 mg, 0.07 mmol) and Cs₂CO₃ (0.12 g, 0.36 mmol) in DMSO (4.5 mL) was degassed under reduced pressure for 15 min. CuI (65.0 mg, 0.34 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. The suspension was heated at 135° C. in a microwave for 150 min. The mixture was then cooled and diluted with ethyl acetate. The resulting mixture was washed sequentially with an aqueous solution of LiCl (5%) and ammonium hydroxide (1%) (2×) and brine. The organic extract was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was dissolved in DCM, treated with charcoal for 20 min and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (DCM to DCM/MeOH 95:5) to give the title compound (34.0 mg, 25%) as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.67-7.53 (m, 2H), 7.33-7.20 (m, 6H), 7.05-6.98 (m, 1H), 6.22 (d, J=6.5 Hz, 1H), 4.71-4.62 (m, 2H), 3.76-3.68 (m, 2H), 3.66 (s, 3H), 3.15-3.12 (m, 2H), 3.02-2.96 (m, 4H), 2.08-2.02 (m, 2H), 1.49-1.27 (m, 9H).

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-phenethylpyrimidin-2 (1H)-one hydrochloride

To a solution of tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (25 mg, 0.068 mmol) in dichloromethane (4.0 mL) was added HCl (2M in diethyl ether, 4.0 mL). The resulting slurry was stirred at room temperature for 2 days and then concentrated under reduced pressure. The resulting residue was purified by semi-preparative HPLC. The clean fractions were combined and concentrated under reduced pressure. The resulting trifluoroacetate salt was treated with aqueous sodium carbonate and extracted with EtOAc (2×). The combined organic extract was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The free base was converted to its HCl salt using HCl in methanol and lypholized to provide the title compound (18.0 mg, 60%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.17 (d, J=6.5 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.32-7.26 (m, 4H), 7.22-7.18 (m, 1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.64 (d, J=6.5 Hz, 1H), 4.56 (s, 2H), 3.79 (s, 3H), 3.60-3.57 (m, 2H), 3.27-3.20 (m, 2H), 3.14-3.06 (m, 4H), 2.23-2.18 (m, 2H); ESI MS m/z 399 [M+H]⁺.

Example 108 Preparation of 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one hydrochloride

a) tert-Butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1 (2H)-yl)-3,4,5, 6-tetrahydroazepino[4,3-b]indole-2 (1H) carboxylate

A suspension of tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (105 mg, 0.28 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one (50 mg, 0.18 mmol), 8-hydroxyquinoline (6 mg, 0.04 mmol) and Cs₂CO₃ (0.12 g, 0.37 mmol) in DMSO (5.0 mL) was degassed under reduced pressure for 30 min. CuI (61.9 mg, 0.33 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. Triethylamine (0.025 mL, 0.18 mmol) was added to the above solution. The resulting suspension was stirred at 135° C. for 20 h. The reaction mixture was cooled and diluted with EtOAc. The resulting solution was washed sequentially with aqueous ammonium chloride and aqueous LiCl (5%), dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was dissolved in DCM, treated with charcoal and purified by preparative TLC (DCM/MeOH 95:5) to afford the title compound (55.0 mg, 72%) as a brown yellow solid and as a mixture of rotamers: ¹H NMR (500 MHz, CDCl₃) δ 9.35 (d, J=1.5 Hz, 1H), 8.75 (d, J=8.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 0.3H), 7.59 (d, J=8.5 Hz, 0.7H), 7.40 (s, 1H), 7.09-7.06 (m, 1H), 6.93 (d, J=7.0 Hz, 1H), 4.72 (s, 0.7H), 4.64 (s, 1.3H), 3.79-3.67 (m, 2H), 3.69 (s, 3H), 2.99-2.97 (m, 2H), 2.08-2.02 (m, 2H), 1.44 (s, 3.3H), 1.38 (s, 5.7H).

b) 1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2 (1H)-one hydrochloride

To a solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-]indole-2(1H) carboxylate (55 mg, 0.13 mmol) in DCM (10 mL) was added TFA (0.50 mL). The reaction solution was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA). The resulting free base was converted to the HCl salt using HCl in methanol to afford the title compound (23.0 mg, 37%) as a brown-reddish solid: ¹H NMR (500 MHz, CD₃OD) δ 9.47 (d, J=1.5 Hz, 1H), 8.80 (dd, J=6.0, 2.0 Hz, 1H), 8.41 (d, J=6.5 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 6.64 (d, J=1.5 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.23 (dd, J=8.5, 2.0 Hz, 1H), 4.58 (s, 2H), 3.72 (s, 3H), 3.61-3.58 (m, 2H), 3.24-3.21 (m, 2H), 2.27-2.20 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 109 Preparation of 4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (125 mg, 0.329 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (85 mg, 0.36 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (123 mg, 70%) as a white solid: ESI MS m/z 535 [M+H]⁺.

b) 4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (123 mg, 0.230 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (93 mg, 86%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (s, 2H), 8.03 (d, J=8.2 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.50 (s, 4H), 7.31 (d, J=8.2 Hz, 1H), 6.17-6.15 (dd, J=7.2, 2.7 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 3.73 (s, 3H), 3.43-3.37 (m, 2H), 3.37-3.31 (m, 2H), 3.30-3.25 (m, 2H), 3.16-3.11 (m, 2H); ESI MS m/z 435 [M+H]⁺; HPLC (Method B) 97.5% (AUC), t_(R)=14.5 min.

Example 110 Preparation of 4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (120 mg, 0.316 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (76 mg, 0.35 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (100 mg, 62%) as a white solid: ESI MS m/z 519 [M+H]⁺.

b) 4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (100 mg, 0.192 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (80 mg, 92%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 2H), 8.06 (d, J=8.2 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.54-7.41 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.29-7.23 (m, 2H), 6.16-6.14 (dd, J=7.2, 2.7 Hz, 1H), 5.99 (d, J=2.6 Hz, 1H), 5.14 (s, 2H), 3.73 (s, 3H), 3.43-3.38 (m, 2H), 3.37-3.31 (m, 2H), 3.30-3.26 (m, 2H), 3.16-3.11 (m, 2H); ESI MS m/z 419 [M+H]⁺; HPLC (Method B) 95.6% (AUC), t_(R)=13.8 min.

Example 111 Preparation of 4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-(3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (120 mg, 0.317 mmol) and 4((3,5-difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (83 mg, 0.35 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (97 mg, 57%) as a white solid: ESI MS m/z 538 [M+H]⁻.

b) 4-(3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 2-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (97 mg, 0.18 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (45 mg, 53%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 2H), 8.59 (d, J=2.3 Hz, 1H), 8.09-8.06 (dt, J=9.5, 2.4 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.15-6.12 (dd, J=7.7, 2.7 Hz, 1H), 6.07 (d, J=2.7 Hz, 1H), 5.28 (s, 2H), 3.73 (s, 3H), 3.42-3.37 (m, 2H), 3.36-3.31 (m, 2H), 3.30-3.26 (m, 2H), 3.16-3.11 (m, 2H); ESI MS m/z 438 [M+H]⁺; HPLC (Method B) 98.6% (AUC), t_(R)=12.5 min.

Example 112 Preparation of 4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (147 mg, 0.386 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (93 mg, 0.43 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (193 mg, 96%) as a yellow oil: ESI MS m/z 519 [M+H]⁺.

b) 4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (193 mg, 0.372 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (139 mg, 82%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (s, 2H), 8.15 (d, J=8.3 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.55-7.51 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.26 (t, J=9.1 Hz, 2H), 6.17-6.14 (dd, J=7.7, 2.6 Hz, 1H), 5.99 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.62-4.50 (m, 2H), 3.76 (s, 3H), 3.49-3.44 (m, 2H), 3.16-3.11 (m, 2H), 2.10-2.04 (m, 2H); ESI MS m/z 419 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=13.6 min.

Example 113 Preparation of 4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (110 mg, 0.289 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (75 mg, 0.318 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 84%) as a colorless oil: ESI MS m/z 535 [M+H]⁺.

b) 4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (130 mg, 0.243 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (91 mg, 80%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.16 (d, J=8.2 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.50 (s, 4H), 7.37 (d, J=8.2 Hz, 1H), 6.18-6.16 (dd, J=7.7, 2.6 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 4.49-4.45 (m, 2H), 3.76 (s, 3H), 3.49-3.42 (m, 2H), 3.16-3.11 (m, 2H), 2.10-2.04 (m, 2H); ESI MS m/z 435 [M+H]⁺; HPLC (Method B)>99% (AUC), t_(R)=14.5 min.

Example 114 Preparation of 4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

a) tert-Butyl 2-(4-(3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (120 mg, 0.32 mmol) and 4-((3,5-difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (83 mg, 0.35 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (139 mg, 82%) as a white foam: ESI MS m/z 537 [M+H]⁺.

b) 4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl 2-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (139 mg, 0.259 mmol) was reacted following the procedure for Example 2 (step e) to provide the title compound (62 mg, 51%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (s, 2H), 8.59 (d, J=2.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 8.09-8.05 (dt, J=9.5, 2.3 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 6.15-6.12 (dd, J=7.7, 2.7 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 5.28 (s, 2H), 4.49-4.45 (m, 2H), 3.73 (s, 3H), 3.48-3.43 (m, 2H), 3.15-3.11 (m, 2H), 2.11-2.05 (m, 2H); ESI MS m/z 438 [M+H]⁺; HPLC (Method B) 96.8% (AUC), t_(R)=12.2 min.

Example 115 Binding Assay for Human Melanin-Concentrating Hormone (MCH-1) Receptor

Evaluation of the affinity of compounds for the human MCH-1 receptor was accomplished using 4-(3,4,5-tritritiumbenzyloxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one and membranes prepared from stable CHO-K1 cells expressing the human MCH-1 receptor obtained from Euroscreen (Batch 1138). Cell membrane homogenates (8.92 μg protein) were incubated for 60 min at 25° C. with 1.4 nM of the [³H]-labeled compound in the absence or presence of the test compound in 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding was determined in the presence of 50 μM 1-(5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)urea. Following incubation, the samples were filtered rapidly under vacuum through Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, and washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting 9,9,0) using a Skatron cell harvester. The filters were counted for radioactivity in a liquid scintillation counter (Tri-Carb 2100TR, Packard) using a scintillation cocktail (Ultima Gold MV, Perkin Elmer).

The results are expressed as a percent inhibition of the control radioligand specific binding. The IC₅₀ value (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficient (n_(H)) were determined by non-linear regression analysis of the competition curve using Hill equation curve fitting. The inhibition constant (K_(i)) was calculated from the Cheng Prusoff equation: (K_(i)=IC₅₀/(1+(L/K_(D))), where L=concentration of radioligand in the assay, and K_(D)=affinity of the radioligand for the receptor.

By methods as described above, the compounds listed in Table 1 were synthesized and tested for biological activity.

TABLE 1 Compounds Tested for Biological Activity Ex. MCH₁ Mass No. Structure K_(i) (nM) Spec ¹H NMR Data 2

14.4 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (br s, 2H), 8.70 (d, J = 9.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.62-7.59 (m, 2H), 7.38 (s, 1H), 7.17 (d, J = 6.5 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 3.72 (s, 3H), 3.43- 3.30 (m, 4H), 3.28-3.25 (m, 2H), 3.17-3.11 (m, 2H) 3

10.1 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.00 (br s, 2H), 8.40 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.61-7.56 (m, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.08-7.05 (m, 2H), 3.72 (s, 3H), 3.43- 3.23 (m, 6H), 3.16-3.11 (m, 2H) 4

7.1 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (d, J = 1.5 Hz, 1H), 9.15-9.02 (m, 2H), 8.49 (dd, J = 8.0, 2.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.60-7.53 (m, 2H), 7.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.80 (dd, J = 7.3, 2.0 Hz, 1H), 3.72 (s, 3H), 3.42-3.37 (m, 2H), 3.36-3.24 (m, 4H), 3.16-3.12 (m, 2H) 5

11.8 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (br s, 2H), 8.89 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.14 (d, J = 7.5 Hz, 1H), 6.01 (s, 1H), 5.35 (s, 2H), 3.69 (s, 3H), 3.41-3.29 (m, 4H), 3.28-3.22 (m, 2H), 3.14-3.10 (m, 2H) 6

131 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 9.10 (br s, 2H), 7.89 (d, J = 7.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.12 (s, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 3.72 (s, 3H), 3.42- 3.33 (m, 4H), 3.29-3.24 (m, 2H), 3.16-3.12 (m, 2H) 7

6.0 386 ¹H NMR (500 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.06 (br s, 2H), 7.57- 7.35 (m, 7H), 7.25 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.11-6.07 (m, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 3.45-3.30 (m, 4H), 3.20-3.15 (m, 2H), 3.12-3.06 (m, 2H) 8

148 426 ¹H NMR (500 MHz, DMSO-d₆) δ 11.27 (s, 1H), 9.09 (br s, 2H), 8.69 (d, J = 9.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 3.41-3.25 (m, 4H), 3.23-3.17 (m, 2H), 3.14-3.09 (m, 2H) 9

1371 425 ¹H NMR (500 MHz, DMSO-d₆) δ 11.26 (br s, 1H), 9.15 (br s, 1H), 9.08- 9.00 (m, 2H), 8.40-8.32 (m, 2H), 7.81 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.08-7.01 (m, 2H), 3.41-3.29 (m, 4H), 3.21-3.14 (m, 2H), 3.13-3.07 (m, 2H) 10

13.4 420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10-8.92 (m, 2H), 8.64 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.85 (ddd, J = 8.5, 8.5, 3.0 Hz, 1H), 7.71 (dd, J = 8.5, 4.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.29 (s, 2H), 3.69 (s, 3H), 3.42-3.32 (m, 4H), 3.27-3.22 (m, 2H), 3.14-3.10 (m, 2H) 11

49.0 385 ¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (br s, 2H), 9.03 (s, 1H), 8.47-8.40 (m, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.71- 7.64 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.04 (dd, J = 8.5, 2.0 Hz, 1H), 6.95 (br s, 1H), 6.78 (dd, J = 7.0, 2.0 Hz, 1H), 3.71 (s, 3H), 3.41-3.31 (m, 4H), 3.29-3.25 (m, 2H), 3.17-3.12 (m, 2H), 2.66 (s, 3H) 12

11.4 424 ¹H NMR (500 MHz, DMSO-d₆) δ 11.25 (s, 1H), 9.15 (br s, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 7.0, 2.0 Hz, 1H), 3.40-3.31 (m, 4H), 3.26-3.18 (m, 2H), 3.09-3.14 (m, 2H) 13

10.3 405 ¹H NMR (500 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.11 (br s, 2H), 8.62 (d, J = 3.0 Hz, 1H), 7.83 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H), 7.65 (dd, J = 9.0, 5.0 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.0, 2.0 Hz, 1H), 6.11 (d, J = 8.0, 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.21 (s, 2H), 3.38- 3.29 (m, 4H), 3.20-3.16 (s, 2H), 3.11- 3.07 (m, 2H) 14

9.6 428 ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (br s, 1H), 7.59-7.35 (m, 8H), 6.95 (dd, J = 8.5, 1.5 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 6.01-5.96 (m, 1H), 5.15 (s, 2H), 3.76-3.05 (m, 13H), 1.31 (t, J = 7.0 Hz, 3H) 15

10.4 442 ¹H NMR (500 MHz, DMSO-d₆) δ 9.89 (br s, 1H), 7.58-7.52 (m, 2H), 7.49- 7.35 (m, 6H), 6.96 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H), 3.77-3.62 (m, 7H), 3.42-3.24 (m, 4H), 3.18-3.11 (m, 1H), 1.37-1.31 (m, 6H) 16

13.7 461 ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br s, 1H), 8.62 (d, J = 3.0 Hz, 1H), 7.83 (ddd, J = 8.5, 8.5, 3.0 Hz, 1H), 7.65 (dd, J = 9.0, 5.0 Hz, 1H), 7.57- 7.52 (m, 2H), 7.44 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.13 (dd, J = 8.0, 3.0 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.22 (s, 2H), 3.78-3.62 (m, 6H), 3.43-3.11 (m, 6H), 1.48-1.39 (m, 6H) 17

7.2 428 ¹H NMR (500 MHz, DMSO-d₆) δ 11.19 (s, 1H), 9.71 (br s, 1H), 7.55- 7.36 (m, 7H), 7.26 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.0, 1.5 Hz, 1H), 6.08 (dd, J = 7.5, 3.0 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 5.14 (s, 2H), 3.75-3.61 (m, 3H), 3.36-3.05 (m, 6H), 1.36-1.30 (m, 6H) 18

11.8 400 ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.59-7.55 (m, 2H), 7.48-7.41 (m, 5H), 7.38-7.36 (m, 1H), 6.97 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.53 (s, 2H), 3.74 (s, 3H), 3.49-3.47 (m, 2H), 2.97 (t, J = 5.0 Hz, 2H), 1.99-1.97 (m, 2H) 19

14.8 419 ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J = 3.0 Hz, 1H), 8.19 (br s, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.58-7.51 (m, 2H), 7.45 (d, J = 1.5 Hz, 1H), 6.95 (dd, J = 8.0, 3.0 Hz, 1H), 6.12 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 5.21 (s, 2H), 4.39 (s, 2H), 3.71 (s, 3H), 3.38-3.36 (m, 2H), 2.95-2.93 (m, 2H), 1.93-1.92 (m, 2H) 20

242 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.12 (br s, 2H), 8.40-8.34 (m, 2H), 7.84 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.10- 7.06 (m, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.50-3.49 (m, 2H), 3.01-2.98 (m, 2H), 2.00-1.98 (m, 2H) 21

4.7 400 ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.38-7.36 (m, 1H), 6.99 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H), 4.44-4.43 (m, 2H), 3.71 (s, 3H), 3.45-3.43 (m, 2H), 3.09 (t, J = 6.0 Hz, 2H), 2.06-2.04 (m, 2H) 22

11.2 419 ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 2H), 8.62 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.85-7.81 (m, 1H), 7.67-7.63 (m, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 6.99 (dd, J = 8.5, 1.5 Hz, 1H), 6.14 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H), 5.22 (s, 2H), 4.43-4.41 (m, 2H), 3.71 (s, 3H), 3.43-3.39 (m, 2H), 3.09 (t, J = 5.0 Hz, 2H), 2.07-2.05 (m, 2H) 23

4.7 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.89 (s, 2H), 8.39 (dd, J = 8.5, 2.0 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.07 (d, J = 7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.47-3.45 (m, 2H), 3.11 (t, J = 5.0 Hz, 2H), 2.08-2.06 (m, 2H) 24

6.4 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s, 2H), 8.89 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 6.99 (dd, J = 8.5, 1.5 Hz, 1H), 6.15 (dd. J = 7.5, 2.5 Hz, 1H), 6.01 (d, J = 2.5 Hz, 1H), 5.35 (s, 2H), 4.42 (s, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H), 3.10-3.09 (m, 2H), 2.07-2.06 (m, 2H) 25

42.3 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 8.93 (s, 2H), 7.89 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.12-7.09 (m, 2H), 6.87 (dd, J = 7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.46-3.40 (m, 2H), 3.12-3.11 (m, 2H), 2.08-2.07 (m, 2H) 26

6.1 438 ¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (s, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 7.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 8.5, 2.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 7.5, 2.5 Hz, 1H), 4.55- 4.46 (m, 2H), 3.73 (s, 3H), 3.46-3.45 (m, 2H), 3.11 (t, J = 5.5 Hz, 2H), 2.08-2.06 (m, 2H) 27

5.3 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.50 (s, 2H), 9.20 (d, J = 2.0 Hz, 1H), 8.50 (dd, J = 8.0, 2.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 8.5, 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 7.5, 2.0 Hz, 1H), 4.42-4.41 (m, 2H), 3.73 (s, 3H), 3.43-3.41 (m, 2H), 3.11 (t, J = 6.0 Hz, 2H), 2.10-2.08 (m, 2H) 28

10.9 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 2H), 8.71 (d, J = 9.0 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 7.0, 2.0 Hz, 1H), 7.13 (dd, J = 8.5, 1.5 Hz, 1H), 4.46-4.45 (m, 2H), 3.75 (s, 3H), 3.46- 3.44 (m, 2H), 3.12 (t, J = 5.5 Hz, 2H), 2.08-2.07 (m, 2H) 29

5.0 414 ¹H NMR (500 MHz, DMSO-d₆) δ 10.02 (br s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.49- 7.36 (m, 6H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.73-4.71 (m, 1H), 4.52-4.47 (m, 1H), 3.72 (s, 3H), 3.68-3.63 (m, 1H), 3.44-3.41 (m, 1H), 3.16-3.03 (m, 2H), 2.81-2.80 (m, 3H), 2.17-2.01 (m, 2H) 30

5.0 428 ¹H NMR (500 MHz, DMSO-d₆) δ 10.34 (br s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.47- 7.41 (m, 5H), 7.39-7.35 (m, 1H), 6.99 (dd, J = 8.0, 1.0 Hz, 1H), 6.09 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.51 (s, 2H), 3.71 (s, 3H), 3.47-3.44 (m, 2H), 3.09-3.08 (m, 2H), 2.97-2.95 (m, 2H), 2.08-2.05 (m, 2H), 1.22 (t, J = 6.5 Hz, 3H) 31

9.4 442 ¹H NMR (500 MHz, DMSO-d₆) δ 9.92 (br s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.50-7.35 (m, 6H), 7.02 (dd, J = 8.0, 1.5 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H), 4.65-4.53 (m, 2H), 3.72 (s, 3H), 3.57- 3.47 (m, 3H), 3.11 (t, J = 6.0 Hz, 2H), 2.24-2.07 (m, 2H), 1.34-1.30 (m, 6H) 32

4.9 416 ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (br s, 2H), 7.75-7.67 (m, 4H), 7.58 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J = 7.0 Hz, 1H), 4.45 (s, 2H), 3.74 (s, 3H), 3.46-3.45 (m, 2H), 3.12-3.10 (m, 2H), 2.54 (s, 3H), 2.07-2.05 (m, 2H) 33

17.5 385 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 9.04 (s, 1H), 8.44 (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.58 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J = 7.0 Hz, 1H), 4.45. (s, 2H), 3.74 (s, 3H), 3.45-3.44 (m, 2H), 3.11-3.09 (m, 2H), 2.66 (s, 3H), 2.08-2.07 (m, 2H) 34

10.6 415 ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 2H), 8.89 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 6.98 (dd, J = 8.5, 1.5 Hz, 1H), 6.14 (dd, J = 8.0, 2.5 Hz, 1H), 6.03 (d, J = 2.0 Hz, 1H), 5.33 (s, 2H), 4.44-4.41 (m, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H), 3.10- 3.08 (m, 2H), 2.76 (s, 3H), 2.08-2.04 (m, 2H) 35

5.8 386 ¹H NMR (500 MHz, DMSO-d₆) δ 11.45 (s, 1H), 8.90 (s, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.28 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.08 (dd, J = 7.5, 3.0 Hz, 1H), 5.95 (d, J = 2.5 Hz, 1H), 5.14 (s, 2H), 4.42-4.41 (m, 2H), 3.47-3.45 (s, 2H), 3.03 (t, J = 5.0 Hz, 2H), 2.01-1.99 (m, 2H) 36

12.2 425 ¹H NMR (500 MHz, DMSO-d₆) δ 11.51 (s, 1H), 9.14 (s, 1H), 8.81 (s, 2H), 8.39 (dd, J = 8.5, 2.0 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.08-7.04 (m, 2H), 4.44 (s, 2H), 3.49-3.47 (m, 2H), 3.06-3.04 (m, 2H), 2.03-2.01 (m, 2H) 37

29.2 426 ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (s, 1H), 8.90 (s, 2H), 8.70 (d, J = 9.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 7.0, 2.0 Hz, 1H), 7.08 (dd, J = 8.5, 2.0 Hz, 1H), 4.44 (s, 2H), 3.48-3.46 (m, 2H), 3.05 (t, J = 5.5 Hz, 2H), 2.03- 2.01 (m, 2H) 38

100 414 ¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 5.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.00 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 2.5Hz, 1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.21-3.10 (m, 2H), 3.12 (t, J = 6.5 Hz, 2H), 2.08-2.07 (m, 2H) 39

16.8 420 ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 2H), 8.63 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.87-7.83 (m, 1H), 7.72-7.69 (m, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.5, 1.5 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 5.29 (s, 2H), 4.44- 4.43 (m, 2H), 3.72 (s, 3H), 3.45-3.43 (m, 2H), 3.10 (t, J = 5.5 Hz, 2H), 2.07-2.05 (m, 2H) 40

7.2 419 ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (s, 2H), 8.62 (d, J = 3.0 Hz, 1H), 7.84- 7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.56 (dd, J = 7.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 6.94 (dd, J = 8.5, 1.5 Hz, 1H), 6.12 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.12 (s, 2H), 3.68 (s, 3H), 3.37-3.32 (m, 4H), 3.26-3.25 (m, 2H), 3.13-3.12 (m, 2H) 41

10.0 438 ¹H NMR (500 MHz, DMSO-d₆) δ 9.29 (s, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.05 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 1.5 Hz, 1H), 6.71 (dd, J = 7.0, 2.0 Hz, 1H), 3.71 (s, 3H), 3.39-3.33 (m, 4H), 3.28-3.27 (m, 2H), 3.16-3.13 (m, 2H) 42

17.8 447 ¹H NMR (500 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.61 (d, J = 2.5 Hz, 1H), 7.82-7.81 (m, 1H), 7.66-7.63 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 6.82 (d, J = 7.0 Hz, 1H), 6.09 (dd, J = 7.5, 3.0 Hz, 1H), 5.95 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H), 3.02-2.98 (m, 1H), 2.86-2.85 (m, 2H), 2.76 (m, 6H), 1.02 (d, J = 6.5 Hz, 6H) 43

8.9 400 ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (br s, 2H), 7.55-7.37 (m, 8H), 6.94 (dd, J = 8.0, 1.0 Hz, 1H), 6.09 (dd, J = 9.0 Hz, 1.0, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.36-3.26 (m, 6H), 3.14-3.12 (m, 2H) 44

11.6 414 ¹H NMR (500 MHz, CD₃OD) δ 7.58 (dd, J = 8.5 Hz, 3.0 Hz, 2H), 7.46 (dd, J = 8.0 Hz, 2.0 Hz, 2H), 7.43-7.39 (m, 3H), 7.37-7.35 (m, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.31 (dd, J = 7.5, 2.5 Hz, 1H), 6.13 (d, J = 1.5 Hz, 1H), 5.18 (s, 2H), 3.81-3.75 (m, 2H), 3.73 (s, 3H), 3.60-3.42 (m 2H), 3.41-3.32 (m, 2H); 3.20-3.10 (m, 2H), 3.08 (s, 3H) 45

26 415 ¹H NMR (500 MHz, DMSO-d₆) δ 9.23 (br s, 2H), 8.81 (s, 1H), 8.40-8.25 (m, 1H), 7.82-7.75 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 2.0, 1H), 6.94 (dd, J = 8.5, 2.0 Hz, 1H), 6.12 (dd, J = 8.0, 3.0 Hz, 1H), 6.02 (d, J = 2.5 Hz, 1H), 5.28 (s, 2H), 3.69 (s, 3H), 3.41-3.29 (m, 4H), 3.28- 3.22 (m, 2H), 3.15-3.10 (m, 2H), 2.68 (s, 3H) 46

47 481 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.49 (dd, J = 8.0, 2.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.53-7.50 (m, 1H), 7.04-6.99 (m, 2H), 6.79 (dd, J = 7.0, 2.0 Hz, 1H), 3.85- 3.65 (m, 7H), 3.14-2.93 (m, 4H), 2.14 (s, 1.2H), 2.09 (s, 1.8H) 47

74 470 ¹H NMR (500 MHz, DMSO-d₆) δ 9.02-8.91 (m, 3H), 8.23 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 2.5, 1H), 7.55-7.51 (m, 2H), 7.09 (dd, J = 8.5, 2.0 Hz, 1H), 6.56 (d, J = 3.0 Hz, 1H), 5.42 (s, 2H), 3.69 (s, 3H), 3.44-3.28 (m, 4H), 3.27-3.21 (m, 2H), 3.13-3.09 (m, 2H) 48

60 461 ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J = 3.0 Hz, 1H), 7.84 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H), 7.66 (dd, J = 8.5, 4.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 3.0, 1.5 Hz, 1H), 6.92-6.88 (m, 1H), 6.12 (dd, J = 7.5, 3.0 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.22 (s, 2H), 3.82-3.76 (m, 2H), 3.75-3.63 (m, 5H), 3.10 (t, J = 5.5, 1H), 3.05-2.98 (m, 2H), 2.93 (t, J = 5.5, 1H), 2.13 (s, 1.5H), 2.08 (s, 1.5H) 49

17 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 8.40 (d, J = 8.0 Hz, 2H), 8.38 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 1.5, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.14 (dd, J = 8.0, 1.5 Hz, 1H), 3.72 (s, 3H), 3.43-3.32 (m, 4H), 3.29-3.24 (m, 2H), 3.16-3.12 (m, 2H) 50

7.4 435 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.78 (d, J = 2.5 Hz, 1H), 8.03 (dd, J = 8.5, 2.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 6.94 (dd, J = 8.0, 1.5 Hz, 1H), 6.14 (dd, J = 7.5, 3.0 Hz, 1H), 5.95 (d, J = 2.5 Hz, 1H), 5.23 (s, 2H), 3.69 (s, 3H), 3.40-3.30 (m, 4H), 3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H) 51

24 468 ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.54-7.50 (m, 2H), 7.45 (d, J = 1.5 Hz, 1H), 6.96 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 3.0 Hz, 1H), 6.00 (d, J = 3.0 Hz, 1H), 5.19 (s, 2H), 3.69 (s, 3H), 3.42-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H) 52

7.8 436 ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.67 (dd, J = 15.0, 9.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.35 (ddd, J = 10.5, 10.5, 2.0 Hz, 1H), 7.18 (ddd, J = 8.5, 8.5, 2.5 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.07 (dd, J = 7.5, 3.0 Hz, 1H), 6.04 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H), 3.69 (s, 3H), 3.41-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.14-3.10 (m, 2H) 53

13 437 ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (br s, 1H), 9.16 (br s, 2H), 7.54-7.32 (m, 6H), 6.96 (d, J = 8.0 Hz, 1H), 4.21-3.44 (m, 9H), 3.42-3.05 (m, 12H) 54

112 428 ¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.19 (dd, J = 2.5, 2.5 Hz, 1H), 6.88-6.83 (m, 1H), 6.07 (dd, J = 8.0, 2.5 Hz, 1H), 5.95 (d, J = 2.5, 1H), 5.14 (s, 2H), 3.76-3.65 (m, 4H), 3.06-3.02 (m, 1H), 2.97-2.91 (m, 2H), 2.87-2.82 (m, 1H), 2.12 (s, 3H) 55

12 452 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (br s, 2H), 7.63 (dd, J = 8.0, 8.0 Hz, 1H), 7.57-7.50 (m, 3H), 7.43 (d, J = 1.5 Hz, 1H), 7.39 (dd, J = 8.5, 2.0 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.08 (dd, J = 7.5, 3.0 Hz, 1H), 6.02 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 3.69 (s, 3H), 3.41-3.31 (m, 4H), 3.28-3.22 (m, 2H), 3.16-3.09 (m, 2H) 56

27 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.69 (s, 1H), 8.37 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.09 (dd, J = 7.5, 2.5 Hz, 1H), 6.01 (s, 1H), 5.30 (s, 2H), 3.69 (s, 3H), 3.42-3.30 (m, 4H), 3.28-3.22 (m, 2H), 3.17-3.09 (m, 2H) 57

7.3 418 ¹H NMR (500 MHz, CD₃OD) δ 7.59 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 8.0, 5.5 Hz, 2H), 7.40 (s, 1H), 7.15 (t, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 1H), 6.30 (t, J = 6.5 Hz, 1H), 6.14 (br s, 1H), 5.16 (s, 2H), 3.74 (s, 3H), 3.54 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5 Hz, 2H), 3.34 (t, J = 5.5 Hz, 2H), 3.24 (t, J = 5.5 Hz, 2H) 58

163 440 ¹H NMR (500 MHz, CD₃OD) δ 9.48 (s, 1H), 8.80 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 6.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 1H), 7.18 (dd, J = 8.5, 1.5 Hz, 1H), 3.78 (s, 3H), 3.56 (t, J = 5.5 Hz, 2H), 3.50 (t, J = 5.5 Hz, 2H), 3.37 (t, J = 5.5 Hz, 2H), 3.26 (t, J = 5.5 Hz, 2H) 59

44 404 ¹H NMR (500 MHz, CD₃OD) δ 8.86 (d, J = 5.5 Hz, 1H), 8.49-8.46 (m, 1H), 8.02 (d, J = 1.0 Hz, 1H), 7.90 (t, J = 6.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.08 (dd, J = 8.5, 2.0 Hz, 1H), 4.54 (s, 2H), 4.13 (s, 2H), 4.09 (t, J = 5.5 Hz, 2H), 3.80 (t, J = 5.0 Hz, 2H), 3.75 (s, 3H), 3.73 (t, J = 5.0 Hz, 2H), 3.63-3.56 (m, 4H), 3.20-3.17 (m, 2H), 2.13-2.09 (m, 2H) 60

21 470 ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (d, J = 1.5 Hz, 1H), 8.87 (s, 2H), 8.22 (dd, J = 8.5, 1.5 Hz, 1H), 8.02-8.00 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.13 (dd, J = 8.5, 2.0 Hz, 1H ), 6.56 (d, J = 3.0 Hz, 1H), 5.41 (s, 2H), 4.44 (s, 2H), 3.72 (s, 3H), 3.47-3.43 (m, 2H), 3.10 (t, J = 5.5 Hz, 2H), 2.08-2.04 (m, 2H) 61

57 461 ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J = 3.0 Hz, 1H), 7.83 (ddd, J = 8.5, 8.5, 3.0 Hz, 1H), 7.66-7.49 (m, 3H), 7.39 (dd, J = 21.0, 2.0 Hz, 1H), 6.93 (ddd, J = 22.5, 8.0, 1.5 Hz, 1H), 6.11 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (dd, J = 5.0, 3.0 Hz, 1H), 5.21 (s, 2H), 4.69-4.68 (m, 2H), 3.78-3.75 (m, 2H), 3.67-3.65 (m, 3H), 3.03-2.96 (m, 2H), 2.09-1.90 (m, 5H) 62

60 481 ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.49 (dd, J = 8.0, 2.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.72-7.49 (m, 2H), 7.07-6.99 (m, 2H), 6.80-6.78 (m, 1H), 4.72-4.70 (m, 2H), 3.79-3.76 (m, 2H), 3.69-3.68 (m, 3H), 3.05- 2.98 (m, 2H), 2.02-1.90 (m, 5H) 63

5 435 ¹H NMR (500 MHz, CD₃OD) δ 8.59 (d, J = 2.4 Hz, 1H), 7.95-7.91 (dd, J = 8.4, 2.4 Hz, 1H), 7.62-7.58 (m, 3H), 7.41 (d, J = 1.6 Hz, 1H), 7.05-7.04 (dd, J = 8.4, 1.6 Hz, 1H), 6.34-6.30 (dd, J = 7.6, 2.7 Hz, 1H), 6.11 (d, J = 2.7 Hz, 1H), 5.26 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.53-3.49 (m, 2H), 3.19- 3.17 (m, 2H), 2.19-2.12 (m, 2H) 64

4.6 437 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.91 (s, 2H), 7.57 (d, J = 8.7 Hz, 1H), 7.40-7.30 (m, 5H), 6.98 (d, J = 8.4 Hz, 1H), 4.42-4.35 (m, 2H), 3.79-3.69 (m, 5H), 3.46-3.36 (m, 2H), 3.26-3.18 (m, 2H), 3.10-3.02 (m, 2H), 2.97-2.76 (m, 4H), 2.72-2.61 (m, 2H), 2.10-1.97 (m, 2H) 65

11 468 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20-9.10 (s, 2H), 7.74 (d, J = 2.1 Hz, 1H), 7.68-7.63 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.52-7.51 (dd, J = 8.2, 2.0 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.01-6.98 (dd, J = 8.4, 1.8 Hz, 1H), 6.12-6.09 (dd, J = 7.6, 2.7 Hz, 1H), 6.01 (d, J = 2.7 Hz, 1H), 5.19 (s, 2H), 4.46-4.39 (s, 2H), 3.71 (s, 3H), 3.47-3.30 (m, 2H), 3.14-3.03 (m, 2H), 2.12-1.99 (m, 2H) 66

7.3 436 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.77 (s, 2H), 7.69-7.63 (m, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.37-7.32 (dt, J = 10.3, 2.5 Hz, 1H), 7.19-7.15 (m, 1H), 7.01-6.99 (dd, J = 8.3, 1.8 Hz, 1H), 6.08-6.06 (dd, J = 7.5, 2.8 Hz, 1H), 6.04 (d, J = 2.8 Hz, 1H), 5.15 (s, 2H), 4.55-4.24 (m, 2H), 3.72 (s, 3H), 3.50-3.41 (m, 2H), 3.10-3.08 (m, 2H), 2.14-1.91 (m, 2H) 67

22 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21-8.98 (s, 2H), 8.69 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.01-6.99 (dd, J = 8.8, 1.8 Hz, 1H), 6.10-6.09 (dd, J = 7.6, 2.8 Hz, 1H), 6.01 (d, J = 2.8 Hz, 1H), 5.30 (s, 2H), 4.43-4.42 (m, 2H), 3.71 (s, 3H), 3.48-3.39 (m, 2H), 3.10-3.07 (m, 2H), 2.14-1.93 (m, 2H) 68

8.2 452 ¹H NMR (500 MHz, DMSO-d₆) δ 9.22-9.04 (s, 2H), 7.65-7.61 (m, 2H), 7.57-7.53 (m, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.39-7.37 (dd, J = 8.1, 1.8 Hz, 1H), 7.00-6.97 (dd, J = 8.2, 1.8 Hz, 1H), 6.09-6.07 (dd, J = 7.6, 2.8 Hz, 1H), 6.03 (d, J = 2.8 Hz, 1H), 5.17 (s, 2H), 4.43-4.41 (m, 2H), 3.71 (s, 3H), 3.38-3.33 (m, 2H), 3.18-3.08 (m, 2H), 2.10-2.06 (m, 2H) 69

12 454 ¹H NMR (500 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.71 (d, J = 8.9 Hz, 1H), 8.47 (d, J = 9.1 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.18-7.17 (dd, J = 7.2, 2.0 Hz, 1H), 7.15-7.14 (dd, J = 8.4, 1.8 Hz, 1H), 4.76 (d, J = 14.3 Hz, 1H), 4.54-4.50 (dd, J = 14.5, 6.5 Hz, 1H), 3.75 (s, 3H), 3.70-3.64 (m, 1H), 3.46- 3.40 (m, 1H), 3.16-3.05 (m, 2H), 2.81 (d, J = 5.0 Hz, 3H), 2.20-2.14 (m, 1H), 2.09-2.00 (m, 1H) 70

8.8 433 ¹H NMR (500 MHz, CD₃OD) δ 8.63 (d, J = 2.7 Hz, 1H), 7.90-7.88 (dd, J = 8.1, 2.8 Hz, 1H), 7.81-7.79 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.11-7.09 (dd, J = 8.4, 1.8 Hz, 1H), 6.57-6.55 (dd, J = 7.5, 2.8 Hz, 1H), 6.34 (d, J = 2.8 Hz, 1H), 5.39 (s, 2H), 4.80 (d, J = 14.8 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 3.85-3.75 (m, 4H), 3.56-3.51 (m, 1H), 3.26-3.15 (m, 2H), 2.79 (s, 3H), 2.57-2.31 (m, 1H), 2.19-2.14 (m, 1H) 71

8.5 483 ¹H NMR (500 MHz, DMSO-d₆) δ 10.52-10.04 (s, 1H), 8.88 (d, J = 1.3 Hz, 1H), 8.20-8.18 (dd, J = 8.1, 1.5 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.02-7.00 (dd, J = 8.6, 1.8 Hz, 1H), 6.16-6.14 (dd, J = 7.6, 2.8 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 5.35 (s, 2H), 4.72 (d, J = 14.2 Hz, 1H), 4.51-4.47 (dd, J = 14.6, 6.5 Hz, 1H), 3.72 (s, 3H), 3.70-3.61 (m, 1H), 3.44-3.38 (m, 1H), 3.11-3.04 (m, 2H), 2.79 (d, J = 4.9 Hz, 3H), 2.17-2.14 (m, 1H), 2.06- 2.03 (m, 1H) 72

7.5 473 ¹H NMR (500 MHz, DMSO-d₆) δ 11.0-10.35 (s, 1H), 8.61 (d, J = 2.9 Hz, 1H), 7.85-7.81 (dt, J = 8.8, 2.9 Hz, 1H), 7.66-7.63 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.01-6.99 (dd, J = 8.4, 1.9 Hz, 1H), 6.14-6.12 (dd, J = 7.6, 1.8 Hz, 1H), 5.96 (d, J = 2.8 Hz, 1H), 5.22 (s, 2H), 4.51 (d, J = 14.2 Hz, 1H), 4.14-4.12 (dd, J = 14.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.67-3.62 (m, 1H), 3.56-3.52 (m, 1H), 3.30- 3.25 (m, 1H), 3.12-3.10 (m, 2H), 2.43-2.39 (m, 1H), 2.29-2.25 (m, 1H), 2.15-2.04 (m, 4H), 1.70-1.68 (m, 1H), 1.62-1.68 (m, 1H) 73

9.4 447 ¹H NMR (500 MHz, DMSO-d₆) δ 10.00-9.95 (s, 1H), 8.62 (s, 1H), 7.85- 7.80 (dt, J = 8.8, 3.0 Hz, 1H), 7.66-7.64 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.14-6.12 (dd, J = 7.6, 2.2 Hz, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.21 (s, 2H), 4.72-4.34 (m, 2H), 3.71 (s, 3H), 3.69-3.63 (m, 2H), 3.14-2.68 (m, 4H), 2.16-1.95 (m, 2H), 1.39-1.15 (m, 3H) 74

10 435 ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.34-7.32 (m, 2H), 7.08-7.04 (m, 3H), 4.75 (d, J = 14.1 Hz, 1H), 4.54 (d, J = 14.4 Hz, 1H), 4.00-3.85 (m, 2H), 3.80-3.70 (m, 5H), 3.60-3.47 (m, 2H), 3.18-3.15 (m, 5H), 3.03-2.90 (m, 3H), 2.95 (s, 3H), 2.39-2.30 (m, 1H), 2.20-2.15 (m, 1H) 75

14 475 ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.32- 7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.61 (d, J = 14.6 Hz, 1H), 4.42 (d, J = 14.6 Hz, 1H), 3.84-3.79 (m, 3H), 3.75 (s, 3H), 3.69-3.65 (m, 2H), 3.63-3.34 (m, 3H), 3.42-2.78 (m, 7H), 2.51-2.38 (m, 1H), 2.38-2.25 (m, 3H), 2.25-2.03 (m, 2H), 1.87-1.76 (m, 2H) 76

9.8 449 ¹H NMR (500 MHz, CD₃OD) δ 7.61 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 1.3 Hz, 1H), 7.31-7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.72 (d, J = 14.9 Hz, 1H), 4.62 (d, J = 14.9 Hz, 1H), 3.92-3.79 (m, 2H), 3.86-3.79 (m, 5H), 3.59-3.47 (m, 2H), 3.26-3.17 (m, 6H), 3.00-2.81 (m, 4H), 2.40-2.24 (m, 1H), 2.24-2.00 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H) 77

11 401 ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.48-7.41 (m, 4H), 7.38 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.16 (dd, J = 7.5, 2.5 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H), 5.16 (s, 2H), 3.73 (s, 3H), 3.39-3.38 (m, 2H), 3.33-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.14 (t, J = 5.5 Hz, 2H) 78

29 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 2H), 9.21 (d, J = 2.0 Hz, 1H), 8.50 (dd, J = 8.5, 2.0 Hz, 1H), 8.10-8.04 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 1.5 Hz, 1H), 6.85 (dd, J = 7.5, 3.5 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H), 3.76 (s, 3H), 3.41-3.40 (m, 2H), 3.33- 3.31 (m, 2H, overlaps with solvent), 3.17 (t, J = 5.5 Hz, 2H) 79

235 441 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 2H), 8.71 (d, J = 9.0 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 7.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.46-3.41 (m, 2H), 3.38-3.34 (m, 2H), 3.32-3.30 (m, 2H, overlapped with solvent), 3.17 (t, J = 6.0 Hz, 2H) 80

69 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 9.15 (dd, J = 1.0, 1.0 Hz, 1H), 8.41-8.35 (m, 2H), 8.09 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 7.0, 2.0 Hz, 1H), 3.76 (s, 3H), 3.42-3.40 (m, 2H), 3.36-3.32 (m, 2H), 3.30-3.28 (m, 2H, overlaps with H₂O), 3.17 (t, J = 6.5 Hz, 2H) 81

33 420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (s, 2H), 8.62 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.19 (dd, J = 7.5, 2.5 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H), 5.23 (s, 2H), 3.73 (s, 3H), 3.40-3.37 (m, 2H), 3.34-3.30 (m, 4H), 3.18-3.14 (m, 2H) 82

53 421 ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s, 2H), 8.64 (d, J = 3.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.85 (ddd, J = 11.5, 8.5, 2.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H), 5.30 (s, 2H), 3.71 (s, 3H), 3.45- 3.39 (m, 2H), 3.38-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.15-3.14 (m, 2H) 83

13 437 ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (br s, 2H), 8.03 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 15.5, 8.5 Hz, 1H), 7.35 (ddd, J = 10.0, 10.0, 2.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.18 (ddd, J = 8.5, 8.5, 2.0 Hz, 1H), 6.14 (dd, J = 8.0, 3.0 Hz, 1H), 6.06 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.59-3.32 (m, 4H), 3.31- 3.26 (m, 2H), 3.17-3.14 (m, 2H) 84

11 453 ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (br s, 2H), 8.03 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 8.0 Hz, 1H), 7.54 (dd, J = 10.0, 1.5 Hz, 1H), 7.39 (br d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.15 (dd, J = 8.0, 3.0 Hz, 1H), 6.05 (d, J = 2.5 Hz, 1H), 5.19 (s, 2H), 3.74 (s, 3H), 3.60-3.32 (m, 4H), 3.31-3.26 (m, 2H), 3.17-3.12 (m, 2H) 85

11 436 ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (br s, 2H), 8.68 (s, 1H), 8.07-8.00 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.20 (br d, J = 6.0 Hz, 1H), 5.97 (br s, 1H), 5.25 (s, 2H), 3.73 (s, 3H), 3.44-3.21 (m, 6H), 3.19-3.11 (m, 2H) 86

16 455 ¹H NMR (500 MHz, DMSO-d₆) δ 10.65 (br s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.33 (d, J = 8.5 Hz, 1H), 6.17 (dd, J = 7.5, 2.0 Hz, 1H), 5.99 (d, J = 2.0 Hz, 1H), 5.17 (s, 2H), 3.99-3.88 (m, 1H), 3.73 (s, 3H), 3.61-3.52 (m, 2H), 3.41-3.17 (m, 4H), 3.15-3.07 (m, 2H), 2.41-2.25 (m, 4H), 1.83-1.60 (m, 2H) 87

6.9 429 ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (br s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.50- 7.36 (m, 5H), 7.32 (d, J = 8.0 Hz, 1H), 6.17 (dd, J = 7.5, 2.5 Hz, 1H), 5.99 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 3.77- 3.62 (m, 5H), 3.50-3.09 (m, 8H), 1.32 (t, J = 7.0 Hz, 3H) 88

8.7 415 ¹H NMR (500 MHz, DMSO-d₆) δ 10.35-10.20 (m, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.32 (d, J = 8.0 Hz, 1H), 6.17 (dd, J = 7.5, 2.5 Hz, 1H), 5.99 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.73-3.63 (m, 2H), 3.43-3.22 (m, 5H), 3.12-3.03 (m, 1H), 2.97 (br s, 3H) 89

15 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (d, J = 2.0 Hz, 1H), 9.04 (s, 2H), 8.50 (dd, J = 8.0, 2.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.47 (d, J =8.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 7.5, 2.0 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.49- 3.46 (m, 2H), 3.17-3.15 (m, 2H), 2.09-2.07 (m, 2H) 90

6.4 401 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 2H), 8.16 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.34 (m, 2H), 6.17 (dd, J = 7.5, 2.5 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.44-3.43 (m, 2H), 3.14-3.12 (m, 2H), 2.09-2.07 (m, 2H) 91

15 420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 2H), 8.62 (d, J = 3.0 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.88-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.19 (dd, J = 8.0, 2.5 Hz, 1H), 5.99 (d, J = 2.5 Hz, 1H), 5.23 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.49-3.40 (m, 2H), 3.36-3.20 (m, 2H), 2.19-2.08 (m, 2H) 92

20 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.89 (br s, 2H), 8.43-8.35 (m, 2H), 8.23 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 1.5, 1H), 7.13 (dd, J = 8.0, 2.0 Hz, 1H), 4.53-4.48 (m, 2H), 3.80 (s, 3H), 3.51-3.45 (m, 2H), 3.19- 3.15 (m, 2H), 2.12-2.08 (m, 2H) 93

26 469 ¹H NMR (500 MHz, DMSO-d₆) δ 8.88-8.81 (m, 2H), 8.16 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.53 (dd, J = 8.0, 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.0, 2.5 Hz, 1H), 6.03 (d, J = 2.5 Hz, 1H), 5.21 (s, 2H), 4.52-4.48 (m, 2H), 3.77 (s, 3H), 3.50-3.43 (m, 2H), 3.19-3.12 (m, 2H), 2.13-2.05 (m, 2H) 94

11 437 ¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (br s, 2H), 8.16 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 15.5, 8.5 Hz, 1H), 7.40-7.34 (m, 2H), 7.18 (ddd, J = 8.5, 8.5, 2.5 Hz, 1H), 7.15 (dd, J = 8.0, 3.0 Hz, 1H), 6.06 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 4.51-4.45 (m, 2H), 3.77 (s, 3H), 3.60-3.42 (m, 2H), 3.17-3.13 (m, 2H), 2.12-2.05 (m, 2H) 95

7.8 439 ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (br s, 2H), 8.22 (d, J = 8.0 Hz, 1H), 8.05-8.00 (m, 3H), 7.89 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0, 1H), 6.90 (s, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.53-4.47 (m, 2H), 3.79 (s, 3H), 3.52-3.25 (m, 2H), 3.20- 3.13 (m, 2H), 2.13-2.07 (m, 2H) 96

9.2 453 ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (br s, 2H), 8.16 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 8.0 Hz, 1H), 7.55 (dd, J = 10.0, 2.0 Hz, 1H), 7.41-7.35 (m, 2H), 6.15 (dd, J = 8.0, 2.5 Hz, 1H), 6.05 (d, J = Hz, 1H), 5.19 (s, 2H), 4.52-4.45 (m, 2H), 3.76 (s, 3H), 3.60-3.31 (m, 2H), 3.17-3.11 (m, 2H), 2.13-2.04 (m, 2H) 97

13 421 ¹H NMR (500 MHz, DMSO-d₆) δ 11.96 (s, 1H), 9.40-9.23 (m, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7.38-7.35 (m, 3H), 7.20 (t, J = 8.6 Hz, 2H), 6.97 (d, J = 8.2 Hz, 1H), 4.23-3.79 (br m, 5H), 3.79- 3.42 (br m, 8H), 3.40-3.34 (m, 2H), 3.29-3.22 (m, 2H), 3.19-3.04 (m, 4H) 98

13 435 ¹H NMR (500 MHz, DMSO-d₆) δ 11.46 (s, 1H), 10.50 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.40-7.33 (m, 3H), 7.25-7.14 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 4.21-3.79 (m, 5H), 3.75-3.39 (m, 7H), 3.38-3.17 (m, 6H), 3.17-3.01 (m, 3H), 2.94 (d, J = 4.9 Hz, 3H) 99

17 449 ¹H NMR (500 MHz, DMSO-d₆) δ 11.44 (s, 1H), 10.16 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.41-7.38 (m, 3H), 7.23-7.15 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 4.23-3.79 (m, 5H), 3.71-3.43 (m, 6H), 3.38-3.17 (m, 9H), 3.17-3.01 (m, 3H), 1.31 (t, J = 7.2 Hz, 3H) 100

10 434 ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 1.5 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.28 (dd, J = 8.0, 3.0 Hz, 1H), 6.11 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.54 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5 Hz, 2H), 3.35-3.33 (m, 2H), 3.23 (t, J = 5.5 Hz, 2H) 101

9.9 399 ¹H NMR (500 MHz, CD₃OD) δ 8.03 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.30-7.28 (m, 4H), 7.22-7.17 (m, 1H), 7.05 (dd, J = 8.5, 2.0 Hz, 1H), 6.56 (d, J = 6.5 Hz, 1H), 3.73 (s, 3H), 3.42- 3.34 (m, 4H), 3.27-3.25 (m, 2H), 3.17- 3.15 (m, 2H), 3.10-3.08 (m, 2H), 3.04-3.02 (m, 2H) 102

22 437 ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 2H), 8.60 (d, J = 2.3 Hz, 8.08-8.06 (m, 1H), 7.56-7.53 (m, 2H), 7.43 (d, J = 1.7 Hz, 1H), 6.95- 6.94 (dd, J = 8.4, 1.8 Hz, 1H), 6.09- 6.05 (m, 2H), 5.27 (d, J = 1.6 Hz, 2H), 3.69 (s, 3H), 3.37-3.35 (m, 2H), 3.35- 3.32 (m, 2H), 3.26-3.24 (m, 2H), 3.13-3.11 (m, 2H) 103

6 418 ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.51 (dd, J = 8.5, 5.5 Hz, 2H), 7.44 (s, 1H), 7.15 (t, J = 8.5 Hz, 2H), 7.06 (dd, J = 8.5, 2.0 Hz, 1H), 6.28 (dd, J = 7.5, 3.0 Hz, 1H), 6.12 (d, J = 3.0 Hz, 1H), 5.16 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.58 (t, J = 5.5 Hz, 2H), 3.20 (t, J = 5.5 Hz, 2H), 2.23- 2.19 (m, 2H) 104

149 433 ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, J = 8.6 Hz, 1H), 8.48 (s, 1H), 7.51-7.46 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.17 (dd, J = 8.5, 1.8 Hz, 1H), 6.12-6.03 (m, 2H), 5.93-5.86 (m, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 3.42-3.34 (m, 2H), 3.09 (t, J = 6.8 Hz, 2H), 2.28-2.19 (m, 2H) 105

7.6 434 ¹H NMR (500 MHz, CD₃OD) δ 7.64 (d, J = 8.0 Hz, 2H), 7.48-7.42 (m, 5H), 7.07 (dd, J = 8.0, 2.0 Hz, 1H), 6.37 (dd, J = 7.5, 2.5 Hz, 1H), 6.17 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.59-3.57 (m, 2H), 3.22-3.19 (m, 2H), 2.26-2.18 (m, 2H) 106

18 437 ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (s, 2H), 8.60 (d, J = 2.3 Hz, 1H), 8.10- 8.06 (dt, J = 10.2, 2.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.01- 6.99 (dd, J = 10.0, 2.6 Hz, 1H), 6.09-6.06 (m, 2H), 5.26 (s, 2H), 4.42-4.40 (m, 2H), 3.71 (s, 3H), 3.44-3.41 (m, 2H), 3.10-3.08 (m, 2H), 2.09-2.03 (m, 2H) 107

9.7 399 ¹H NMR (500 MHz, CD₃OD) δ 8.17 (d, J = 6.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.32-7.26 (m, 4H), 7.22-7.18 (m, 1H), 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 6.64 (d, J = 6.5 Hz, 1H), 4.56 (s, 2H), 3.79 (s, 3H), 3.60-3.57 (m, 2H), 3.27-3.20 (m, 2H), 3.14-3.06 (m, 4H), 2.23-2.18 (m, 2H) 108

60 440 ¹H NMR (500 MHz, CD₃OD) δ 9.47 (d, J = 1.5 Hz, 1H), 8.80 (dd, J = 6.0, 2.0 Hz, 1H), 8.41 (d, J =6.5 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 6.64 (d, J = 1.5 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H), 4.58 (s, 2H), 3.72 (s, 3H), 3.61-3.58 (m, 2H), 3.24-3.21 (m, 2H), 2.27-2.20 (m, 2H) 109

9.6 435 ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (s, 2H), 8.03 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.50 (s, 4H), 7.31 (d, J = 8.2 Hz, 1H) 6.17-6.15 (dd, J = 7.2, 2.7 Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.17 (s, 2H), 3.73 (s, 3H), 3.43- 3.37 (m, 2H), 3.37-3.31 (m, 2H), 3.30-3.25 (m, 2H), 3.16-3.11 (m, 2H) 110

12 419 ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 2H), 8.06 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.54-7.41 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.29- 7.23 (m, 2H), 6.16-6.14 (dd, J = 7.2, 2.7 Hz, 1H), 5.99 (d, J = 2.6 Hz, 1H), 5.14 (s, 2H), 3.73 (s, 3H), 3.43-3.38 (m, 2H), 3.37-3.31 (m, 2H), 3.30-3.26 (m, 2H), 3.16-3.11 (m, 2H) 111

71 438 ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 2H), 8.59 (d, J = 2.3 Hz, 1H), 8.09- 8.06 (dt, J = 9.5, 2.4 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.15-6.12 (dd, J = 7.7, 2.7 Hz, 1H), 6.07 (d, J = 2.7 Hz, 1H), 5.28 (s, 2H), 3.73 (s, 3H), 3.42-3.37 (m, 2H), 3.36-3.31 (m, 2H), 3.30-3.26 (m, 2H), 3.16-3.11 (m, 2H) 112

8.9 419 ¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (s, 2H), 8.15 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.55-7.51 (m, 2H), 7.37 (d, J =8.0 Hz, 1H), 7.26 (t, J = 9.1 Hz, 2H), 6.17-6.14 (dd, J = 7.7, 2.6 Hz, 1H), 5.99 (d, J = 2.7 Hz, 1H), 5.15 (s, 2H), 4.62-4.50 (m, 2H), 3.76 (s, 3H), 3.49-3.44 (m, 2H), 3.16- 3.11 (m, 2H), 2.10-2.04 (m, 2H) 113

5.9 435 ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.16 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.50 (s, 4H), 7.37 (d, J = 8.2 Hz, 1H), 6.18-6.16 (dd, J = 7.7, 2.6 Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.17 (s, 2H), 4.49-4.45 (m, 2H), 3.76 (s, 3H), 3.49-3.42 (m, 2H), 3.16- 3.11 (m, 2H), 2.10-2.04 (m, 2H) 114

44 438 ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (s, 2H), 8.59 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.09-8.05 (dt, J = 9.5, 2.3 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.15-6.12 (dd, J = 7.7, 2.7 Hz, 1H), 6.08 (d, J = 2.7 Hz, 1H), 5.28 (s, 2H), 4.49-4.45 (m, 2H), 3.73 (s, 3H), 3.48-3.43 (m, 2H), 3.15-3.11 (m, 2H), 2.11-2.05 (m, 2H)

As compounds that bind strongly to MCH-1, compounds of formula I are expected to be effective in reducing obesity.

The present invention is not limited to the compounds found in the above examples, and many other compounds falling within the scope of the invention may also be prepared using the procedures set forth in the above synthetic schemes. The preparation of additional compounds of formula (I) using these methods will be apparent to one of ordinary skill in the chemical arts.

Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow. 

What is claimed:
 1. A compound of formula (I):

wherein R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R² is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R³ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁴ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁵ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; R⁶ is independently selected at each location from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁷ is optionally present and, if present, is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁹ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹⁰ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹¹ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹² is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹³ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; R¹⁶ and R¹⁷ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; R¹⁸ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹; G is —NR⁸—CR⁹R¹⁰—CR¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—, with the proviso that when G is —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not —C(O)NR¹³R¹⁴; X is CR¹⁸, C(R¹⁸)₂, N, Or NR¹⁸; Y is CR¹⁸, C, or N; Z is CH, C, or N; L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond; A is CH, C, or N; B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3 substituents selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and —CN; n is 0, 1, 2, or 3; p is from 1 to 4; q is 0, 1, or 2; and

represents an optional double bond, or an oxide thereof or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein G is —NR⁸—CR⁹R¹⁰—CR¹¹R¹²—.
 3. The compound according to claim 2, wherein R⁸ is H or C₁-C₆ alkyl, R⁹ is H, R¹⁰ is H, R¹¹ is H, and —R¹² is H.
 4. The compound according to claim 1, wherein G is —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—.
 5. The compound according to claim 4, wherein R⁸ is H or C₁-C₆ alkyl, R⁹ is H, R¹⁰ is H, R¹¹ is H, and —R¹² is H.
 6. The compound according to claim 1, wherein G is —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—.
 7. The compound according to claim 6, wherein R⁸ is H or C₁-C₆ alkyl, R⁹ is H, R¹⁰ is H, R¹¹ is H, and —R¹² is H.
 8. The compound according to claim 1, wherein R¹ is H.
 9. The compound according to claim 1, wherein R¹ is C₁-C₆ alkyl.
 10. The compound according to claim 1, wherein R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl.
 11. The compound according to claim 1, wherein R⁸ is H or C₁-C₆ alkyl.
 12. The compound according to claim 1, wherein R⁴ and R⁵ are combined to form an oxo group.
 13. The compound according to claim 1, wherein X is N, CH, or CH₂.
 14. The compound according to claim 1, wherein Y is N, C, or CH.
 15. The compound according to claim 1, wherein L is a bond.
 16. The compound according to claim 1, wherein L is —CH₂—O—.
 17. The compound according to claim 1, wherein L is —CH₂—CH₂—.
 18. The compound according to claim 1, wherein B is phenyl, pyridinyl, pyridazinyl, or pyrimidinyl.
 19. The compound according to claim 1, wherein B is unsubstituted.
 20. The compound according to claim 1, wherein B is substituted with at least one substituent selected from trifluoromethyl, chloro, fluoro, methyl, and methanethio.
 21. The compound according to claim 1, wherein B is selected from the group consisting of phenyl, 4-(trifluoromethyl)phenyl, 4-(methylthio)-phenyl, 5-(trifluoromethyl)pyridin-2-yl, 2-(trifluoromethyl)-pyrimidin-5-yl, 6-(trifluoromethyl)pyridazin-3-yl, 5-fluoro-pyridin-2-yl, 6-methylpyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl, 5-chloro-pyridin-2-yl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, 4-chloro-phenyl, 4-chloro-2-fluoro-phenyl, 3,5-dichloro-pyridin-2-yl, 4-fluoro-phenyl, pyridin-2-yl, and 3,5-difluoro-pyridin-2-yl.
 22. The compound according to claim 1, wherein the compound has the structure:


23. The compound according to claim 1, wherein the compound is selected from the group consisting of


24. The compound according to claim 1, wherein the compound is selected from the group consisting of


25. The compound according to claim 1, wherein the compound is selected from the group consisting of


26. The compound according to claim 1, wherein the compound is an HCl salt.
 27. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
 28. A method of treating obesity in a subject in need of weight loss comprising: selecting a patient in need of weight loss, and administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 29. A method of treating obesity in a subject who has experienced weight loss comprising: selecting a patient who has experienced weight loss, and administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 30. A method of treating anxiety comprising: selecting a patient with anxiety, and administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 31. A method of treating depression comprising: selecting a patient with depression, and administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 32. A process for the preparation of a product compound of formula (I):

wherein R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R² is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R³ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁴ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁵ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; R⁶ is independently selected at each location from the group consisting of H, halogen, —OR¹³, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁷ is optionally present and, if present, is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R⁹ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹⁰ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹¹ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹² is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹³ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; R¹⁶ and R¹⁷ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy; R¹⁸ is selected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹; G is —NR⁸—CR⁹R¹⁰—CR¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—, with the proviso that when G is —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not —C(O)NR¹³R¹⁴; X is CR¹⁸, C(R¹⁸)₂, N, Or NR¹⁸; Y is CR¹⁸, C, or N; Z is C, CH, or N; L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond; A is C, CH, or N; B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3 substituents selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl, halogen, —CF₃, and —CN; n is 0, 1, 2, or 3; p is from 1 to 4; q is 0, 1, or 2; and

represents an optional double bond, said process comprising: treating a first intermediate of formula (II):

wherein Q is a halogen, under conditions effective to form the compound of formula (I). 